Skip to main content

Main menu

  • Home
  • Content
    • Current
    • Archive
  • Info for
    • Authors
    • Subscribers
    • Advertisers
    • Editorial Board
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics

User menu

  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Anticancer Research
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics
  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Anticancer Research

Advanced Search

  • Home
  • Content
    • Current
    • Archive
  • Info for
    • Authors
    • Subscribers
    • Advertisers
    • Editorial Board
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Visit us on Facebook
  • Follow us on Linkedin
Review ArticlePart BR

Calcium, Vitamin D and Cancer

MEINRAD PETERLIK, WILLIAM B. GRANT and HEIDE S. CROSS
Anticancer Research September 2009, 29 (9) 3687-3698;
MEINRAD PETERLIK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: meinrad.peterlik@meduniwien.ac.at
WILLIAM B. GRANT
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
HEIDE S. CROSS
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

A low vitamin D status and inadequate calcium intake are important risk factors for various types of cancer. Ecological studies using solar UV-B exposure as an index of vitamin D3 photoproduction in the skin found a highly significant inverse association between UV-B and mortality in fifteen types of cancer. Of these, colon, rectal, breast, gastric, endometrial, renal and ovarian cancer exhibit a significant inverse relationship between incidence and oral intake of calcium. In addition, lung and endometrial cancer as well as multiple myeloma are considered calcium and vitamin D sensitive. Studies on tissue-specific expression of the CYP27B1-encoded 25-hdroxyvitamin D-1α-hydroxylase and of the extracellular calcium-sensing receptor (CaR) have led to an understanding how locally produced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and extracellular Ca2+ act jointly as key regulators of cellular proliferation, differentiation and function. Thus, impairment of antimitogenic, proapoptotic and prodifferentiating signaling from the 1,25(OH)2D3-activated vitamin D receptor (VDR) and from the CaR in vitamin D and calcium insufficiency has been implicated in the pathogenesis of the aforementioned types of cancer. 1,25(OH)2D3 and calcium interact in modulating cell growth in different ways: (i) Signaling pathways from the VDR and the CaR converge on the same downstream elements, e.g. of the canonical Wnt pathway; (ii) high extracellular calcium modulates extrarenal vitamin D metabolism in favor of higher local steady-state concentrations of 1,25(OH)2D3; (iii) 1,25(OH)2D3 may up-regulate expression of the CaR and thus augment CaR-mediated antiproliferative responses to high extracellular Ca2+. This can explain why combined supplementation is required for optimal chemoprevention of cancer by calcium and vitamin D.

  • Vitamin D insufficiency
  • calcium intake
  • dairy calcium
  • calcium-sensing receptor
  • extrarenal 25-hydroxyvitamin D-1α-hydroxylase
  • 1,25-dihydroxyvitamin D3
  • 25-hydroxyvitamin D-24-hydroxylase
  • review

A nutritional calcium deficit and a compromised vitamin D status are risk factors for multiple chronic diseases, including various types of malignancy [for review, (1)]. A strong association between a low vitamin D status and cancer incidence or mortality has been reported for colon, rectal, breast, prostate and ovarian cancer (2). In addition, vitamin D insufficiency apparently contributes to the pathogenesis of gastric, lung, esophageal, pancreatic, renal and endometrial cancer, as well as non-Hodgkin's lymphoma (3). There is evidence that poor calcium nutrition is a significant risk factor for total cancer incidence (4), and, in particular, for colorectal (5-9), breast (10-12) and renal (13, 14) cancer. Low calcium intake may also contribute to the development of gastric (15), pancreatic (16) and ovarian cancer (17, 18), and to some extent of endometrial (19, 20) lung (21) and prostate (22) cancer, as well as multiple myeloma (23) (cf. Table 1).

Relevance of Adequate Calcium Intake for Control of Cellular Growth

Different levels of daily calcium intake according to age, sex, and hormonal status are currently recommended as a preventive measure against a negative calcium balance (24). A minimum of 1,000 mg calcium per day is required for healthy adults until age 60 years, while higher values apply for people of advanced age, or women during pregnancy and lactation as well as after menopause. Evidence is accumulating that calcium malnutrition is not only encountered in the elderly (25) but is widespread also in the younger population in Europe as well as in North America (26, 27).

A concept how signals from nutritional calcium are transduced to organs and cell systems distant from the intestinal lumen was not available until Brown and colleagues (28) cloned an extracellular calcium-sensing receptor (CaR) from the bovine parathyroid gland. Many other cells also express this receptor, among them normal and neoplastic human renal (28), gastric (29), large intestinal epithelial (30), mammary gland (31), ovarian (32), prostate gland (33), and pancreatic duct cells (34). The CaR transduces minute changes in extracellular fluid Ca2+ concentrations to stimulatory and inhibitory G proteins in a large variety of intracellular signaling pathways. Consequently, when extracellular Ca2+ drops due to inadequate supply from dietary sources, not only will the parathyroid gland release more PTH, but cellular homeostasis and functions in many other tissues will also be affected. CaR-mediated changes in proliferation, differentiation, and apoptosis may thus contribute to the pathogenesis of various types of cancer (Table I).

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table I.

Effect of calcium from different sources on cancer risk (with references).

Relevance of Adequate Plasma Vitamin D Levels for Organ-specific Control of Cell Growth

Regardless whether synthesized in the epidermis or absorbed from the diet, vitamin D3 is converted in the liver to 25-hydroxyvitamin D3 (25(OH)D3). The serum level of 25(OH)D (the term 25(OH)D is used to denote the sum of 25(OH)D3 and 25(OH)D2, the latter from dictary sources) is considered a reliable indicator of the vitamin D status of a person. The terms vitamin D insufficiency or inadequacy are used to describe a condition in which insufficient circulating 25(OH)D is available for optimal intracellular production of 1,25(OH)2D3 at extrarenal sites. As detailed in the following, this explains why serum levels of 25(OH)D are inversely associated with the incidence of many chronic diseases (1). Importantly, low serum 25(OH)D has been shown to be a reliable predictor of all-cause mortality (35, 36). Conservative calculations of the set point between vitamin D insufficiency and optimal vitamin D supply arrived at a value of 30 nM 25(OH)D (37) but there is increasing evidence that for optimal health outcomes serum 25(OH)D should be maintained at much higher levels, i.e. between 60 and 100 nM (38-40).

Vitamin D insufficiency is frequently observed in individuals with limited sun exposure, as in the chronically ill, in immobilized or housebound elderly people. Yet a compromised vitamin D status is also a common phenomenon in the free living normal population at any age (26, 41-43).

Conversion of 25(OH)D3 to 1,25(OH)2D3 is catalyzed by the CYP27B1-encoded enzyme 25(OH)D-1α-hydroxylase and occurs primarily in the kidney. However, many extrarenal cells also biosynthesize 1,25(OH)2D3. Examples are normal and neoplastic epithelial cells of the skin (44), of the gastrointestinal tract (45-48) and of female and male reproductive organs (49-51). Renal CYP27B1 activity is tightly regulated by serum Ca2+ and parathyroid hormone (PTH), as well as by feed-back inhibition from 1,25(OH)2D3. Therefore, circulating 1,25(OH)2D3 can be maintained in the normal range, 75-200 pM, even when serum levels of 25(OH)D are relatively low (52). Extrarenal synthesis of 1,25(OH)2D3 is, however, regulated differently. Expression of CYP27B1 at extrarenal sites can be modulated independently of circulating PTH, Ca2+ (53) or 1,25(OH)2D3 (54, 55), so that 25(OH)D-1α-hydroxylase activity depends largely on ambient 25(OH)D3 levels. This may explain why the incidence of vitamin D insufficiency-related cancer of the colorectum (56), breast (57) and prostate gland (58) is correlated primarily with low serum 25(OH)D, and only to a lesser extent with low 1,25(OH)2D3 (59). Altogether, at low serum levels of 25(OH)D, CYP27B1 activity in extrarenal cellular systems may be not high enough to achieve steady-state tissue concentrations of 1,25(OH)2D3 necessary to regulate cellular growth, differentiation and apoptosis. Therefore, vitamin D insufficiency plays an important pathogenic role in many malignancies (2, 3) (see also Table I).

Combined Vitamin D and Calcium Insufficiency

In a population-based cross-sectional study on calcium and vitamin D status of healthy adults of both sexes (26, 60), daily calcium consumption was below recommended levels in 81% of the cohort. In the same study, 26% of all participants were considered vitamin D-insufficient. When calcium intake by 25(OH)D serum levels was calculated, 23% of the entire cohort exhibited combined vitamin D and calcium insufficiency (1) and, therefore, may have a particularly high risk for vitamin D and calcium insufficiency-related cancer (Table I). This notion is strongly supported by the report of Lappe et al. that only combined calcium and vitamin D supplements could significantly reduce the general incidence of cancer of the breast, lung, colon, and uterus as well as of the lymphoid and myeloid system (61). In particular, Cho et al. (6) concluded from an analysis of pooled primary data from 10 cohort studies, in which more than half a million individuals were followed up for 6-16 years, that optimal risk reduction for colorectal cancer necessitates high intake levels of both vitamin D and calcium. This notion was shown to be valid not only for Western but also for Asian populations (7, 8). Bérubé et al. (62) studied the relation of separate and combined intakes of vitamin D and calcium by pre-menopausal women on mammographic breast density as a surrogate marker for breast cancer risk. They found that the negative association between dietary vitamin D intake and breast density tended to be stronger when calcium intake levels were higher and vice versa.

Mechanisms of Calcium and Vitamin D Action in Control of Neoplastic Cell Growth

The CaR is an essential part of an intricate network of calcium signaling pathways that control normal and cancer cell growth (63-66), Depending on cell-specific coupling to appropriate G-proteins, activation of the CaR by elevated extracellular Ca2+ reduces the rate of cellular proliferation as in human colon carcinoma (67, 68) or ovarian surface epithelial cells (69), but may also stimulate cell growth as in malignant Leydig cells (70) and protect from apoptosis, for example, in prostate cancer cells (71).

1,25(OH)2D3 exerts antiproliferative effects on cancer cells by modulating the transcriptional activity of key genes involved in cell cycle control [for review see (72)]. 1,25(OH)2D3 may also suppress tumor growth and progression indirectly by facilitating immunocytotoxic killing of tumor cells: 1,25(OH)2D3 reduces levels of immunosuppressive CD34+ lymphocytes, which normally limit the cytotoxic activity of infiltrating tumor-specific CD8+ T lymphocytes (73). The nearly ubiquitous expression of CYP27B1 (74) and the importance of intrinsic 1,25(OH)2D3 production in controlling cell proliferation may explain why vitamin D insufficiency increases the risk of malignancies in many organs and biological systems.

Colorectal cancer. In 1980 Garland and Garland proposed that sunlight and vitamin D can protect against colon cancer (75). This hypothesis had gained strong support when in 1985 Garland et al. (76) published the results of a 19-year prospective trial showing that low dietary intakes of vitamin D and of calcium are associated with a significant risk of colorectal cancer. Since then many other observational studies reported a strong association between incidence or mortality for colorectal cancer and a low vitamin D status [for review, see (2)] or, respectively, low calcium intake (6-8). It should be noted that vitamin D insufficiency increases cancer risk in the colon and in the rectum, whereas calcium insufficiency does so in the colon and possibly not in the rectum (77-79).

Studies from our laboratory (80-83) have shown that 1,25(OH)2D3 inhibits growth and promotes differentiation of human colon adenoma and carcinoma cells by inhibiting up-regulation of cyclin D1 expression, a key element in cell cycle control. A number of intracellular proliferative signaling pathways, viz. the Raf-1/MEK1/ERK and STAT-3 pathways, converge at c-Myc (84) and engage cyclin D1 as a common downstream effector. 1,25(OH)2D3 therefore counteracts mitogenesis whatever the nature of cellular growth promoting factors is (85). Another antimitogenic mechanism of 1,25(OH)2D3 involves direct interaction with growth factor receptor-activated pathways. For example, in human colon adenocarcinoma-derived Caco-2 cells, 1,25(OH)2D3 diminishes the number of ligand-occupied epidermal growth factor receptors (EGFRs) (85).

A role of the CaR in mediating the chemopreventive effects of calcium was suggested by the significant association between genetic variants of the CaR and advanced colorectal adenoma (86). Moreover, certain single nucleotide polymorphisms in the CaR gene were found to be associated with an increased risk of cancer in the proximal colon (87). Neoplastic human colonocytes express CaR at the mRNA and protein levels as long as they retain a certain degree of differentiation (88, 89). The sequence of events downstream of CaR activation that actually link CaR to cell cycle control starts with inhibition of phospholipase A2 activity (67), which would reduce the amount of arachidonic acid available for synthesis of proliferation-stimulating prostaglandins. Subsequent down-regulation of c-myc proto-oncogene expression (30), activation of the cyclin-dependent kinase inhibitor p21 (53) and inhibition of cyclin D1 finally leads to cell cycle arrest at the G1/S-phase transition. CaR-activated pro-differentiating signaling in colonocytes involves inhibition of the Wnt/β-catenin pathway by down-regulation of T-cell transcription factor (TCF)-4 with subsequent induction of E-cadherin expression (68, 90). Interestingly, part of the antiproliferative action of 1,25(OH)2D3 has been traced to a VDR-mediated negative effect on TCF-4 (68, 91) (Figure 1).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Co-operative signalling from 1,25(OH)2D3/VDR and Ca2+/CaR inhibits proliferation and promotes differentiation of human colon cancer cells.

Three modes of interaction between 1,25(OH)2D3 and Ca2+ in modulating cell growth and differentiation have been identified in the colon mucosa: (i) As detailed before, activation of the VDR or the CaR is transduced to the same key elements of antiproliferative and prodifferentiating signaling, i.e. c-Myc and cyclin D1 as well as TCF-4 and E-cadherin (Figure 1). (ii) High luminal calcium not only inhibits cellular growth by activating the CaR, but at the same time suppresses the vitamin D catabolizing enzyme 25(OH)D-24-hydroxylase (CYP24); this very likely leads to higher steady-state local concentrations of 1,25(OH)2D3 (53, 92). (iii) 1,25(OH)2D3 may up-regulate expression of the CaR (93) and thus augment CaR-mediated antiproliferative responses to high extracellular Ca2+.

Elucidation of the molecular and cellular mechanisms of action of calcium and vitamin D on growth rate and differentiation of human colon carcinoma cells helped to understand why the efficiency of vitamin D in reducing the risk of colorectal cancer depends very much on the calcium status of an individual and vice versa, so that optimal prevention of the disease necessitates high intake levels of both vitamin D and calcium. Cho et al. (6) analyzed pooled primary data from 10 large cohort studies and found, as illustrated in Figure 2, that a significant effect of calcium intake on colorectal cancer risk can be observed only at the highest level of vitamin D intake. Additional strong support for a joint action of calcium and vitamin D in the prevention of colorectal carcinogenesis is provided by two recent large cohort studies from Japan (7, 8).

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Relative risk of colorectal cancer for total calcium intake by levels of total vitamin D intake. Data are from Table IV in Ishihara et al. (8).

Breast cancer. The long-standing assumption that low vitamin D intake is associated with increased breast cancer risk (94-96) has been supported by a recent study of Shin et al. (10), who showed in an analysis of data from the Nurses' Health Study that premenopausal women with a daily vitamin D intake of >500 IU had a significantly lower risk (RR=0.72) of breast cancer than those ingesting only 150 IU and less. The importance of adequate vitamin D supply for the prevention of breast cancer had been particularly emphasized by Grant (97-99) and Garland et al. (2), who estimated that in the U.S., more than 10% of premature mortality from breast cancer could be attributed to insufficient UV-B radiation.

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Proapoptotic signalling from VDR/1,25(OH)2D3 and Ca2+/CaR in MCF-7 breast cancer cells.

Lin et al. (12) studied the effects of vitamin D and calcium intake from nutrient sources and supplements on breast cancer risk in a large cohort of premenopausal women. They found that higher intakes of total calcium and vitamin D were associated with a lower risk of premenopausal breast cancer (RR=0.61; 95% CI: 0.40-0.92, for calcium, and RR=0.65; 95% CI: 0.42-1.00, for vitamin D intake). McCullough et al. (11) analyzed data from nearly 70,000 postmenopausal women participating in the Cancer Prevention Study II Nutrition Cohort and found a moderately lower risk of breast cancer (RR=0.80) with intake of dietary calcium >1,250 mg/day compared to <500 mg/day. This association was even stronger (RR=0.67) in women with estrogen receptor (ER)-positive tumors.

1,25(OH)2D3 exerts antiproliferative effects on breast cancer cells by changing the expression of oncogenes and tumor suppressor genes, such as retinoblastoma tumor suppressor protein, cyclins A1, D1, D3 and E1, as well as cyclin-dependent kinase inhibitors p21WAF-1/CIP-1 and p27kip1 (72, 100). In addition, 1,25(OH)2D3 induces apoptosis in breast cancer cells by stimulating Ca2+ release from intracellular stores. The resulting rise in cytosolic Ca2+ triggers calpain-mediated caspase-independent programmed cell death (101).

A role for a functional CaR in breast cancer can be inferred from the fact that in premenopausal women the serum calcium level varies inversely with breast cancer risk in a concentration-dependent manner (102). Both normal and malignant mammary gland epithelial cells are endowed with the CaR (31). However, little is known how the CaR mediates changes in ambient Ca2+ to regulate cellular growth. In MCF-7 breast cancer cells, activation of the CaR is transduced into enhanced Ca2+ influx across the plasma membrane through non-selective cation channels (103). The resulting increase in intracellular Ca2+ may conceivably activate proapoptotic intracellular signaling (63), similar to that caused by 1,25(OH)2D3 (101) (Figure 3).

Figure 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4.

Effect of Ca intake on breast density in premenopausal women by levels of vitamin D intake. Adapted from Table III in Bérubé et al. (62).

The effect of the apparent cross-talk between Ca2+/CaR and 1,25(OH)2 D3/VDR signaling on cytosolic Ca may explain, at least in part, how vitamin D and calcium together efficiently inhibit mammary gland cell growth in vivo. Bérubé et al. (62) found that combined intake of vitamin D and calcium by pre-menopausal women was superior to separate intakes in reducing mammographic breast density (Figure 4). Synergistic actions of calcium and vitamin D are likely to be the reason why high intake of low-fat dairy products is associated with a reduced risk of breast cancer in premenopausal women (10) (cf. Figure 5).

Prostate cancer. Although there is firm evidence that low 25(OH)D serum levels are associated with increased risk of and mortality from prostate cancer (58, 104), rather conflicting data have been reported on the effect of calcium intake on the incidence and prognosis of prostate cancer. Giovannucci et al. (105) found a positive correlation between calcium intake from food sources and supplements and risk of prostate cancer. Skinner and Schwartz analyzing data from the National Health and Nutrition Examination Surveys I and III found that high serum calcium is associated with an increased risk of fatal prostate cancer though not with incident prostate cancer (106, 107). Any notion that high serum calcium has a direct cancerogenic effect is not supported by the report of Leifsson and Ahren (108) that in men under 50 years of age the risk of obtaining a diagnosis of malignant disease in the future was not found to increase with rising serum Ca2+ levels. No effect of calcium intake on prostate cancer risk was seen in two large observational studies (109, 110). In a meta-analysis of 45 observational studies, Huncharek et al. (111) found that calcium data from cohort studies were heterogenous. Case control analyses, however, demonstrated no association between calcium and increased risk of prostate cancer. Notably, data from a randomized prospective clinical trial (22) indicated that calcium supplements did not increase but even appeared to lower the incidence of prostate cancer.

Figure 5.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5.

Effect of Ca from different sources on breast cancer risk in premenopausal women. Data are from Table III in Shin et al. (10).

These discordant findings on the influence of calcium on prostate cancer risk may be better understood if one considers the possibility of a dual effect of CaR activation on prostate epithelial cell growth. It is not clear whether activation of the CaR on prostate epithelial cells by high calcium will only inhibit cell growth. Due to transactivation by the CaR of the EGFR (112), high calcium concentrations could also induce proliferation and prevent apoptosis (71). In the presence of EGFR agonists, activation of the CaR could then effectively counteract any VDR-mediated growth inhibitory effect of 1,25(OH)2D3 and vice versa (Figure 6). We hypothesize that depending on the outcome of CaR-mediated growth modulation, calcium intake could be associated with an increased risk (105), with no risk (109, 110), or even with a reduced risk (22) of prostate cancer.

Figure 6.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 6.

Antagonistic effects of Ca2+ and vitamin D on cellular homeostasis in prostate cancer.

Other types of cancer. Vitamin D sensitivity has been reported in many malignancies, including endometrial, gastric, ovarian, pancreatic and renal cancer (3, 113-115). Since all of these cancer cells express a functional CaR (29, 32-34), an inverse relation between calcium intake and disease incidence is not unexpected. In a prospective study on a large cohort of post-menopausal women, Prineas et al. (13) found that total dietary calcium was an independent predictor of renal cell carcinoma incidence. Women taking >1,280 mg calcium per day had a 35% lower risk of the disease compared to those on less than 800 mg/day. The beneficial effect of calcium supplements on renal cell carcinoma risk particularly in women was confirmed by a case-control study by Hu et al. (14). Isolated reports on a risk-reducing effect of nutrient calcium on head and neck, esophageal (4), gastric (15), pancreatic (16), ovarian (17), endometrial (19, 20) cancer certainly need to be confirmed by further studies.

Calcium, Vitamin D and Cancer Prevention

Because Ca2+/CaR and VDR/1,25(OH)2D3 signaling interact positively in growth control of cancer cells (Figures 1 and 3), it can be expected that an adequate vitamin D status is required to achieve the benefits of high calcium intake and vice versa. In fact, there is evidence from epidemiological as well as interventional studies that optimal reduction of cancer risk can be achieved only by a high intake of both calcium and vitamin D. For example, in a study on the effect of vitamin D and calcium supplementation on recurrence of colorectal adenomas, Grau et al. (116) found that calcium supplementation was only effective in patients if their serum 25(OH)D values were normal. Conversely, high 25(OH)D levels were associated with a reduced risk of adenoma recurrence only among those on calcium supplements. Holt et al. (117) gave adenomatous polyp patients high doses of supplemental calcium in combination with vitamin D. After six months of treatment they observed a significant reduction in the rate of polyp formation that was accompanied by an increase in expression of apoptotic markers. Similar results were reported recently by Fedirko et al. (118). Cho et al. (6) concluded from an analysis of pooled primary data from 10 cohort studies with a follow-up of more than half a million individuals for 6-16 years, that optimal risk reduction for colorectal cancer necessitates high intake levels of both vitamin D and calcium (Figure 2).

Figure 7.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 7.

Differential effect of Ca intake on risk of colon cancer in women and men.

It is well known that women are protected particularly from more aggressive colorectal cancer [cf. (119)]. It has been argued that this may be a result of long-time exposure to estrogens before menopause or of hormone replacement therapy thereafter (120, 121). Antiproliferative effects of 17β-estradiol are mediated through the ER-β, which is the predominant ER subtype in the human colon mucosa (122). In addition, there is evidence to suggest that the chemopreventive effect of estrogen against colorectal cancer is mediated in part through VDR-activated antiproliferative intracellular signaling from 1,25(OH)2D3: Preliminary data from our laboratory indicate that 17β-estradiol up-regulates CYP27B1 expression in human rectal epithelium in vivo (unpublished observation). 17β-Estradiol and ER-β-activating phytoestrogens such as genistein have been shown to increase VDR and CYP27B1 expression and activity in human colonocytes (123). Similar effects were seen in MCF-7 breast cancer cells (123) and DU-145 prostate cancer cells (124).

Estrogens stimulate intestinal calcium absorption by a vitamin D-independent mechanism (125) and have thus a positive effect on calcium metabolism in women. This may be the reason that dietary calcium is approximately twice as effective in reducing colon cancer risk in women compared to men (Figure 7). Taken together, by appropriate modulation of vitamin D metabolism and by improving the calcium status, estrogenic compounds have the potential to intensify the antiproliferative actions of vitamin D and calcium. Based on these findings, Cross et al. (126, 127) developed the concept of chemoprevention of colorectal, breast and prostate cancer by phytoestrogens, vitamin D and calcium.

Berubé et al. (62) concluded from the results of their study on the effects of calcium and/or vitamin D on breast density that increasing the intake of both vitamin D and calcium “may represent a safe and inexpensive strategy for breast cancer prevention”. A way to raise calcium and vitamin D intake is by increased consumption of milk and dairy products. There is firm evidence that higher consumption of milk and dairy products reduces the risk of colorectal cancer (128). Studies by Kesse et al. (9), Shin et al. (10) and McCullough et al. (11) strongly suggest that the protective effect of dairy products on colon and breast cancer is due to dietary calcium in combination with some other components in dairy products, one of which could be vitamin D. Figure 5 indicates that calcium is more effective in reducing breast cancer risk when derived from dairy than from other sources. However, it must be noted that milk and dairy products contain not only vitamin D3 and its biologically more active metabolites but may also contain carcinogenic substances such as fat and fatty acids, insulin-like growth factor and bovine growth hormone (129). Therefore, dairy product consumption, while not a risk factor for breast cancer (129), may be a risk factor for pancreatic cancer (130, 131) and possibly for prostate cancer. Using mortality and ecological data from 41 countries, Grant (132) identified the non-fat portion of milk as the dairy component with the highest association with prostate cancer. This may explain why dairy calcium seems to be associated with a modest risk of non-aggressive prostate cancer (133).

Lappe et al. (61) reported evidence from a four-year, population-based, double-blind, randomized placebo-controlled trial that in post-menopausal women combined high-dose calcium (1,500 mg/day) and vitamin D3 (1,100 IU/day) supplementation reduced the cumulative risk of cancer of the breast, lung, colon, uterus, lymphoid and myeloid system to 0.232 after four years of trial. Survival at the end of the study was significantly higher in the calcium/vitamin D treatment group compared to the placebo group. This study provides an impressive example of the efficacy of combined calcium and vitamin D supplementation in cancer prevention in general.

We want to emphasize that high intake of vitamin D together with calcium is relevant not only for cancer prevention and, as is well known, for osteoporosis therapy, but has benefits for many other calcium and vitamin D insufficiency-related pathologies (for review see (1)), including infectious, chronic inflammatory and autoimmune diseases as well as incipient and end-stage cardiovascular disorders.

Footnotes

  • Disclosure

    WBG receives funding from the UV Foundation (McLean, VA, USA), the Vitamin D Society (Canada), and the European Sunlight Association (Brussels).

  • Received April 15, 2009.
  • Revision received June 8, 2009.
  • Accepted June 18, 2009.
  • Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved

References

  1. 1.↵
    1. Peterlik M,
    2. Cross HS
    : Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 35: 290-304, 2005.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Garland CF,
    2. Garland FC,
    3. Gorham ED,
    4. Lipkin M,
    5. Newmark H,
    6. Mohr SB,
    7. Holick MF
    : The role of vitamin D in cancer prevention. Am J Public Health 96: 252-261, 2006.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Grant WB,
    2. Garland CF
    : The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res 26: 2687-2699, 2006.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Park Y,
    2. Leitzmann MF,
    3. Subar AF,
    4. Hollenbeck A,
    5. Schatzkin A
    : Dairy food, calcium, and risk of cancer in the NIH-AARP Diet and Health Study. Arch Intern Med 169: 391-401, 2009.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Wu K,
    2. Willett WC,
    3. Fuchs CS,
    4. Colditz GA,
    5. Giovannucci EL
    : Calcium intake and risk of colon cancer in women and men. J Natl Cancer Inst 94: 437-446, 2002.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Cho E,
    2. Smith-Warner SA,
    3. Spiegelman D,
    4. Beeson WL,
    5. van den Brandt PA,
    6. Colditz GA,
    7. Folsom AR,
    8. Fraser GE,
    9. Freudenheim JL,
    10. Giovannucci E,
    11. Goldbohm RA,
    12. Graham S,
    13. Miller AB,
    14. Pietinen P,
    15. Potter JD,
    16. Rohan TE,
    17. Terry P,
    18. Toniolo P,
    19. Virtanen MJ,
    20. Willett WC,
    21. Wolk A,
    22. Wu K,
    23. Yaun SS,
    24. Zeleniuch-Jacquotte A,
    25. Hunter DJ
    : Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst 96: 1015-1022, 2004.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Mizoue T,
    2. Kimura Y,
    3. Toyomura K,
    4. Nagano J,
    5. Kono S,
    6. Mibu R,
    7. Tanaka M,
    8. Kakeji Y,
    9. Maehara Y,
    10. Okamura T,
    11. Ikejiri K,
    12. Futami K,
    13. Yasunami Y,
    14. Maekawa T,
    15. Takenaka K,
    16. Ichimiya H,
    17. Imaizumi N
    : Calcium, dairy foods, vitamin D, and colorectal cancer risk: the Fukuoka colorectal cancer study. Cancer Epidemiol Biomarkers Prev 17: 2800-2807, 2008.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Ishihara J,
    2. Inoue M,
    3. Iwasaki M,
    4. Sasazuki S,
    5. Tsugane S
    : Dietary calcium, vitamin D, and the risk of colorectal cancer. Am J Clin Nutr 88: 1576-1583, 2008.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Kesse E,
    2. Boutron-Ruault MC,
    3. Norat T,
    4. Riboli E,
    5. Clavel-Chapelon F
    : Dietary calcium, phosphorus, vitamin D, dairy products and the risk of colorectal adenoma and cancer among French women of the E3N-EPIC prospective study. Int J Cancer 117: 137-144, 2005.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Shin MH,
    2. Holmes MD,
    3. Hankinson SE,
    4. Wu K,
    5. Colditz GA,
    6. Willett WC
    : Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst 94: 1301-1311, 2002.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. McCullough ML,
    2. Rodriguez C,
    3. Diver WR,
    4. Feigelson HS,
    5. Stevens VL,
    6. Thun MJ,
    7. Calle EE
    : Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 14: 2898-2904, 2005.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Lin J,
    2. Manson JE,
    3. Lee IM,
    4. Cook NR,
    5. Buring JE,
    6. Zhang SM
    : Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 167: 1050-1059, 2007.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Prineas RJ,
    2. Folsom AR,
    3. Zhang ZM,
    4. Sellers TA,
    5. Potter J
    : Nutrition and other risk factors for renal cell carcinoma in postmenopausal women. Epidemiology 8: 31-36 1997.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Hu J,
    2. Mao Y,
    3. White K
    : Diet and vitamin or mineral supplements and risk of renal cell carcinoma in Canada. Cancer Causes Control 14: 705-714, 2003.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Yang CY,
    2. Cheng MF,
    3. Tsai SS,
    4. Hsieh YL
    : Calcium, magnesium, and nitrate in drinking water and gastric cancer mortality. Jpn J Cancer Res 89: 124-130, 1998.
    OpenUrlCrossRef
  16. 16.↵
    1. Yang CY,
    2. Chiu HF,
    3. Cheng MF,
    4. Tsai SS,
    5. Hung CF,
    6. Tseng YT
    : Pancreatic cancer mortality and total hardness levels in Taiwan's drinking water. J Toxicol Environ Health A 56: 361-369, 1999.
    OpenUrlPubMed
  17. 17.↵
    1. Koralek DO,
    2. Bertone-Johnson ER,
    3. Leitzmann MF,
    4. Sturgeon SR,
    5. Lacey JV Jr.,
    6. Schairer C,
    7. Schatzkin A
    : Relationship between calcium, lactose, vitamin D, and dairy products and ovarian cancer. Nutr Cancer 56: 22-30, 2006.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Goodman MT,
    2. Wu AH,
    3. Tung KH,
    4. McDuffie K,
    5. Kolonel LN,
    6. Nomura AM,
    7. Terada K,
    8. Wilkens LR,
    9. Murphy S,
    10. Hankin JH
    : Association of dairy products, lactose, and calcium with the risk of ovarian cancer. Am J Epidemiol 156: 148-157, 2002.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Terry P,
    2. Vainio H,
    3. Wolk A,
    4. Weiderpass E
    : Dietary factors in relation to endometrial cancer: a nationwide case-control study in Sweden. Nutr Cancer 42: 25-32, 2002.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. McCullough ML,
    2. Bandera EV,
    3. Moore DF,
    4. Kushi LH
    : Vitamin D and calcium intake in relation to risk of endometrial cancer: a systematic review of the literature. Prev Med 46: 298-302, 2008.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Koo LC
    : Dietary habits and lung cancer risk among Chinese females in Hong Kong who never smoked. Nutr Cancer 11: 155-172, 1988.
    OpenUrlPubMed
  22. 22.↵
    1. Baron JA,
    2. Beach M,
    3. Wallace K,
    4. Grau MV,
    5. Sandler RS,
    6. Mandel JS,
    7. Heber D,
    8. Greenberg ER
    : Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 14: 586-589, 2005.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Hosgood HD 3rd.,
    2. Baris D,
    3. Zahm SH,
    4. Zheng T,
    5. Cross AJ
    : Diet and risk of multiple myeloma in Connecticut women. Cancer Causes Control 18: 1065-1076, 2007.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Favus MJ
    1. Gagel RF
    : Mineral and vitamin D RDA for infants children and adults. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2nd ed., Favus MJ (ed.), New York, Raven Press, p. 413, 1993.
  25. 25.↵
    1. Barrett-Connor E
    : The RDA for calcium in the elderly: too little, too late. Calcif Tissue Int 44: 303-307, 1989.
    OpenUrlPubMed
  26. 26.↵
    1. Kudlacek S,
    2. Schneider B,
    3. Peterlik M,
    4. Leb G,
    5. Klaushofer K,
    6. Weber K,
    7. Woloszczuk W,
    8. Willvonseder R
    : Assessment of vitamin D and calcium status in healthy adult Austrians. Eur J Clin Invest 33: 323-331, 2003.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Ma J,
    2. Johns RA,
    3. Stafford RS
    : Americans are not meeting current calcium recommendations. Am J Clin Nutr 85: 1361-1366, 2007.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Brown EM,
    2. Gamba G,
    3. Riccardi D,
    4. Lombardi M,
    5. Butters R,
    6. Kifor O,
    7. Sun A,
    8. Hediger MA,
    9. Lytton J,
    10. Hebert SC
    : Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 366: 575-580, 1993.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Hebert SC,
    2. Cheng S,
    3. Geibel J
    : Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract. Cell Calcium 35: 239-247, 2004.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Kállay E,
    2. Kifor O,
    3. Chattopadhyay N,
    4. Brown EM,
    5. Bischof MG,
    6. Peterlik M,
    7. Cross HS
    : Calcium-dependent c-myc proto-oncogene expression and proliferation of Caco-2 cells: a role for a luminal extracellular calcium-sensing receptor. Biochem Biophys Res Commun 232: 80-83, 1997.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Cheng I,
    2. Klingensmith ME,
    3. Chattopadhyay N,
    4. Kifor O,
    5. Butters RR,
    6. Soybel DI,
    7. Brown EM
    : Identification and localization of the extracellular calcium-sensing receptor in human breast. J Clin Endocrinol Metab 83: 703-707, 1998.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. McNeil L,
    2. Hobson S,
    3. Nipper V,
    4. Rodland KD
    : Functional calcium-sensing receptor expression in ovarian surface epithelial cells. Am J Obstet Gynecol 178: 305-313, 1998.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Sanders JL,
    2. Chattopadhyay N,
    3. Kifor O,
    4. Yamaguchi T,
    5. Brown EM
    : Ca2+-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells. Am J Physiol Endocrinol Metab 281: E1267-1274, 2001.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Racz GZ,
    2. Kittel A,
    3. Riccardi D,
    4. Case RM,
    5. Elliott AC,
    6. Varga G
    : Extracellular calcium sensing receptor in human pancreatic cells. Gut 51: 705-711, 2002.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Dobnig H,
    2. Pilz S,
    3. Scharnagl H,
    4. Renner W,
    5. Seelhorst U,
    6. Wellnitz B,
    7. Kinkeldei J,
    8. Boehm BO,
    9. Weihrauch G,
    10. Maerz W
    : Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med 168: 1340-1349, 2008.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Melamed ML,
    2. Michos ED,
    3. Post W,
    4. Astor B
    : 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 168: 1629-1637, 2008.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Chapuy MC,
    2. Preziosi P,
    3. Maamer M,
    4. Arnaud S,
    5. Galan P,
    6. Hercberg S,
    7. Meunier PJ
    : Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7: 439-43, 1997.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Bischoff-Ferrari HA,
    2. Giovannucci E,
    3. Willett WC,
    4. Dietrich T,
    5. Dawson-Hughes B
    : Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84: 18-28, 2006.
    OpenUrlAbstract/FREE Full Text
  39. 39.
    1. Dawson-Hughes B,
    2. Heaney RP,
    3. Holick MF,
    4. Lips P,
    5. Meunier PJ,
    6. Vieth R
    : Estimates of optimal vitamin D status. Osteoporos Int 16: 713-716, 2005.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Gorham ED,
    2. Garland CF,
    3. Garland FC,
    4. Grant WB,
    5. Mohr SB,
    6. Lipkin M,
    7. Newmark HL,
    8. Giovannucci E,
    9. Wei M,
    10. Holick MF
    : Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med 32: 210-216, 2007.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Dawson-Hughes B,
    2. Harris SS,
    3. Dallal GE
    : Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr 65: 67-71, 1997.
    OpenUrlAbstract/FREE Full Text
  42. 42.
    1. Hypponen E,
    2. Power C
    : Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 85: 860-868, 2007.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Lamberg-Allardt CJ,
    2. Outila TA,
    3. Karkkainen MU,
    4. Rita HJ,
    5. Valsta LM
    : Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe? J Bone Miner Res 16: 2066-2073, 2001.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Pillai S,
    2. Bikle DD,
    3. Elias PM
    : 1,25-Dihydroxyvitamin D production and receptor binding in human keratinocytes varies with differentiation. J Biol Chem 263: 5390-5395, 1988.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Cross HS,
    2. Peterlik M,
    3. Reddy GS,
    4. Schuster I
    : Vitamin D metabolism in human colon adenocarcinoma-derived Caco-2 cells: expression of 25-hydroxyvitamin D3-1α-hydroxylase activity and regulation of side-chain metabolism. J Steroid Biochem Mol Biol 62: 21-28, 1997.
    OpenUrlCrossRefPubMed
  46. 46.
    1. Zehnder D,
    2. Bland R,
    3. Williams MC,
    4. McNinch RW,
    5. Howie AJ,
    6. Stewart PM,
    7. Hewison M
    : Extrarenal expression of 25-hydroxyvitamin D3-1 alpha-hydroxylase. J Clin Endocrinol Metab 86: 888-894, 2001.
    OpenUrlCrossRefPubMed
  47. 47.
    1. Radermacher J,
    2. Diesel B,
    3. Seifert M,
    4. Tilgen W,
    5. Reichrath J,
    6. Fischer U,
    7. Meese E
    : Expression analysis of CYP27B1 in tumor biopsies and cell cultures. Anticancer Res 26: 2683-2686, 2006.
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    1. Schwartz GG,
    2. Eads D,
    3. Rao A,
    4. Cramer SD,
    5. Willingham MC,
    6. Chen TC,
    7. Jamieson DP,
    8. Wang L,
    9. Burnstein KL,
    10. et al.
    : Pancreatic cancer cells express 25-hydroxyvitamin D-1 α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. Carcinogenesis 25: 1015-1026, 2004.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    1. Becker S,
    2. Cordes T,
    3. Diesing D,
    4. Diedrich K,
    5. Friedrich M
    : Expression of 25 hydroxyvitamin D3-1α-hydroxylase in human endometrial tissue. J Steroid Biochem Mol Biol 103: 771-775, 2007.
    OpenUrlCrossRefPubMed
  50. 50.
    1. Friedrich M,
    2. Rafi L,
    3. Mitschele T,
    4. Tilgen W,
    5. Schmidt W,
    6. Reichrath J
    : Analysis of the vitamin D system in cervical carcinomas, breast cancer and ovarian cancer. Recent Results Cancer Res 164: 239-246, 2003.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Schwartz GG,
    2. Whitlatch LW,
    3. Chen TC,
    4. Lokeshwar BL,
    5. Holick MF
    : Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev 7: 391-395, 1998.
    OpenUrlAbstract/FREE Full Text
  52. 52.↵
    1. Hansen KE,
    2. Jones AN,
    3. Lindstrom MJ,
    4. Davis LA,
    5. Engelke JA,
    6. Shafer MM
    : Vitamin D insufficiency: disease or no disease? J Bone Miner Res 23: 1052-1060, 2008.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Kállay E,
    2. Bises G,
    3. Bajna E,
    4. Bieglmayer C,
    5. Gerdenitsch W,
    6. Steffan I,
    7. Kato S,
    8. Armbrecht HJ,
    9. Cross HS
    : Colon-specific regulation of vitamin D hydroxylases - a possible approach for tumor prevention. Carcinogenesis 26: 1581-1589, 2005.
    OpenUrlAbstract/FREE Full Text
  54. 54.↵
    1. Anderson PH,
    2. O'Loughlin PD,
    3. May BK,
    4. Morris HA
    : Modulation of CYP27B1 and CYP24 mRNA expression in bone is independent of circulating 1,25(OH)2D3 levels. Bone 36: 654-662, 2005.
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Lechner D,
    2. Kállay E,
    3. Cross HS
    : 1α,25-Dihydroxyvitamin D3 down-regulates CYP27B1 and induces CYP24A1 in colon cells. Mol Cell Endocrinol 263: 55-64, 2007.
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Feskanich D,
    2. Ma J,
    3. Fuchs CS,
    4. Kirkner GJ,
    5. Hankinson SE,
    6. Hollis BW,
    7. Giovannucci EL
    : Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 13: 1502-1508, 2004.
    OpenUrlAbstract/FREE Full Text
  57. 57.↵
    1. Bertone-Johnson ER,
    2. Chen WY,
    3. Holick MF,
    4. Hollis BW,
    5. Colditz GA,
    6. Willett WC,
    7. Hankinson SE
    : Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 14: 1991-1997, 2005.
    OpenUrlAbstract/FREE Full Text
  58. 58.↵
    1. Tuohimaa P,
    2. Tenkanen L,
    3. Ahonen M,
    4. Lumme S,
    5. Jellum E,
    6. Hallmans G,
    7. Stattin P,
    8. Harvei S,
    9. Hakulinen T,
    10. Luostarinen T,
    11. Dillner J,
    12. Lehtinen M,
    13. Hakama M
    : Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 108: 104-108, 2004.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Pilz S,
    2. Dobnig H,
    3. Winklhofer-Roob B,
    4. Riedmuller G,
    5. Fischer JE,
    6. Seelhorst U,
    7. Wellnitz B,
    8. Boehm BO,
    9. März W
    : Low serum levels of 25-hydroxyvitamin D predict fatal cancer in patients referred to coronary angiography. Cancer Epidemiol Biomarkers Prev 17: 1228-1233, 2008
    OpenUrlAbstract/FREE Full Text
  60. 60.↵
    1. Kudlacek S,
    2. Schneider B,
    3. Peterlik M,
    4. Leb G,
    5. Klaushofer K,
    6. Weber K,
    7. Woloszczuk W,
    8. Willvonseder R
    : Normative data of bone mineral density in an unselected adult Austrian population. Eur J Clin Invest 33: 332-339, 2003.
    OpenUrlCrossRefPubMed
  61. 61.↵
    1. Lappe JM,
    2. Travers-Gustafson D,
    3. Davies KM,
    4. Recker RR,
    5. Heaney RP
    : Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85: 1586-1591, 2007.
    OpenUrlAbstract/FREE Full Text
  62. 62.↵
    1. Berubé S,
    2. Diorio C,
    3. Masse B,
    4. Hebert-Croteau N,
    5. Byrne C,
    6. Cote G,
    7. Pollak M,
    8. Yaffe M,
    9. Brisson J
    : Vitamin D and calcium intakes from food or supplements and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14: 1653-1659, 2005.
    OpenUrlAbstract/FREE Full Text
  63. 63.↵
    1. Roderick HL,
    2. Cook SJ
    : Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival: Nat Rev Cancer 8: 361-375, 2008.
    OpenUrlCrossRefPubMed
  64. 64.
    1. Rodland KD
    : The role of the calcium-sensing receptor in cancer. Cell Calcium 35: 291-295, 2004.
    OpenUrlCrossRefPubMed
  65. 65.
    1. Tfelt-Hansen J,
    2. Brown EM
    : The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 42: 35-70, 2005.
    OpenUrlCrossRefPubMed
  66. 66.↵
    1. Capiod T,
    2. Shuba Y,
    3. Skryma R,
    4. Prevarskaya N
    : Calcium signalling and cancer cell growth. Subcell Biochem 45: 405-427, 2007.
    OpenUrlCrossRefPubMed
  67. 67.↵
    1. Kállay E,
    2. Bonner E,
    3. Wrba F,
    4. Thakker RV,
    5. Peterlik M,
    6. Cross HS
    : Molecular and functional characterization of the extracellular calcium-sensing receptor in human colon cancer cells. Oncol Res 13: 551-559, 2003.
    OpenUrlPubMed
  68. 68.↵
    1. Chakrabarty S,
    2. Wang H,
    3. Canaff L,
    4. Hendy GN,
    5. Appelman H,
    6. Varani J
    : Calcium sensing receptor in human colon carcinoma: interaction with Ca2+ and 1,25-dihydroxyvitamin D3. Cancer Res 65: 493-498, 2005.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. Bilderback TR,
    2. Lee F,
    3. Auersperg N,
    4. Rodland KD
    : Phosphatidylinositol 3-kinase-dependent, MEK-independent proliferation in response to CaR activation. Am J Physiol Cell Physiol 283: C282-288, 2002.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. Tfelt-Hansen J,
    2. Yano S,
    3. John Macleod R,
    4. Smajilovic S,
    5. Chattopadhyay N,
    6. Brown EM
    : High calcium activates the EGF receptor potentially through the calcium-sensing receptor in Leydig cancer cells. Growth Factors 23: 117-123, 2005.
    OpenUrlCrossRefPubMed
  71. 71.↵
    1. Lin KI,
    2. Chattopadhyay N,
    3. Bai M,
    4. Alvarez R,
    5. Dang CV,
    6. Baraban JM,
    7. Brown EM,
    8. Ratan RR
    : Elevated extracellular calcium can prevent apoptosis via the calcium-sensing receptor. Biochem Biophys Res Commun 249: 325-331, 1998.
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Deeb KK,
    2. Trump DL,
    3. Johnson CS
    : Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7: 684-700, 2007.
    OpenUrlCrossRefPubMed
  73. 73.↵
    1. Wiers K,
    2. Wright MA,
    3. Vellody K,
    4. Young MR
    : Failure of tumor-reactive lymph node cells to kill tumor in the presence of immune-suppressive CD34+ cells can be overcome with vitamin D3 treatment to diminish CD34+ cell levels. Clin Exp Metastasis 16: 275-282, 1998.
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Hewison M,
    2. Burke F,
    3. Evans KN,
    4. Lammas DA,
    5. Sansom DM,
    6. Liu P,
    7. Modlin RL,
    8. Adams JS
    : Extrarenal 25-hydroxyvitamin D3-1α-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 103: 316-321, 2007.
    OpenUrlCrossRefPubMed
  75. 75.↵
    1. Garland CF,
    2. Garland FC
    : Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 9: 227-231, 1980.
    OpenUrlAbstract/FREE Full Text
  76. 76.↵
    1. Garland C,
    2. Shekelle RB,
    3. Barrett-Connor E,
    4. Criqui MH,
    5. Rossof AH,
    6. Paul O
    : Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet 1: 307-309, 1985.
    OpenUrlCrossRefPubMed
  77. 77.↵
    1. Wakai K,
    2. Hirose K,
    3. Matsuo K,
    4. Ito H,
    5. Kuriki K,
    6. Suzuki T,
    7. Kato T,
    8. Hirai T,
    9. Kanemitsu Y,
    10. Tajima K
    : Dietary risk factors for colon and rectal cancers: a comparative case-control study. J Epidemiol 16: 125-135, 2006.
    OpenUrlCrossRefPubMed
  78. 78.
    1. Jarvinen R,
    2. Knekt P,
    3. Hakulinen T,
    4. Aromaa A
    : Prospective study on milk products, calcium and cancers of the colon and rectum. Eur J Clin Nutr 55: 1000-1007, 2001.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. Sweeney C,
    2. Curtin K,
    3. Murtaugh MA,
    4. Caan BJ,
    5. Potter JD,
    6. Slattery ML
    : Haplotype analysis of common vitamin D receptor variants and colon and rectal cancers. Cancer Epidemiol Biomarkers Prev 15: 744-749, 2006.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    1. Cross HS,
    2. Pavelka M,
    3. Slavik J,
    4. Peterlik M
    : Growth control of human colon cancer cells by vitamin D and calcium in vitro. J Natl Cancer Inst 84: 1355-1357, 1992.
    OpenUrlFREE Full Text
  81. 81.
    1. Cross HS,
    2. Hulla W,
    3. Tong WM,
    4. Peterlik M
    : Growth regulation of human colon adenocarcinoma-derived cells by calcium, vitamin D and epidermal growth factor. J Nutr 125: 2004S-2008S, 1995.
    OpenUrlAbstract/FREE Full Text
  82. 82.
    1. Hulla W,
    2. Kállay E,
    3. Krugluger W,
    4. Peterlik M,
    5. Cross HS
    : Growth control of human colon-adenocarcinoma-derived Caco-2 cells by vitamin-D compounds and extracellular calcium in vitro: relation to c-myc oncogene and vitamin D receptor expression. Int J Cancer 62: 711-716, 1995.
    OpenUrlPubMed
  83. 83.↵
    1. Tong WM,
    2. Hofer H,
    3. Ellinger A,
    4. Peterlik M,
    5. Cross HS
    : Mechanism of antimitogenic action of vitamin D in human colon carcinoma cells: relevance for suppression of epidermal growth factor-stimulated cell growth. Oncol Res 11: 77-84, 1999.
    OpenUrlPubMed
  84. 84.↵
    1. Bowman T,
    2. Broome MA,
    3. Sinibaldi D,
    4. Wharton W,
    5. Pledger WJ,
    6. Sedivy JM,
    7. Irby R,
    8. Yeatman T,
    9. Courtneidge SA,
    10. Jove R
    : Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA 98: 7319-7324, 2001.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    1. Tong WM,
    2. Kállay E,
    3. Hofer H,
    4. Hulla W,
    5. Manhardt T,
    6. Peterlik M,
    7. Cross HS
    : Growth regulation of human colon cancer cells by epidermal growth factor and 1,25-dihydroxyvitamin D3 is mediated by mutual modulation of receptor expression. Eur J Cancer 34: 2119-2125, 1998.
    OpenUrlCrossRefPubMed
  86. 86.↵
    1. Peters U,
    2. Chatterjee N,
    3. Yeager M,
    4. Chanock SJ,
    5. Schoen RE,
    6. McGlynn KA,
    7. Church TR,
    8. Weissfeld JL,
    9. Schatzkin A,
    10. Hayes RB
    : Association of genetic variants in the calcium-sensing receptor with risk of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 13: 2181-186, 2004.
    OpenUrlAbstract/FREE Full Text
  87. 87.↵
    1. Dong LM,
    2. Ulrich CM,
    3. Hsu L,
    4. Duggan DJ,
    5. Benitez DS,
    6. White E,
    7. Slattery ML,
    8. Caan BJ,
    9. Potter JD,
    10. Peters U
    : Genetic variation in calcium-sensing receptor and risk for colon cancer. Cancer Epidemiol Biomarkers Prev 17: 2755-2765, 2008.
    OpenUrlAbstract/FREE Full Text
  88. 88.↵
    1. Kállay E,
    2. Bajna E,
    3. Wrba F,
    4. Kriwanek S,
    5. Peterlik M,
    6. Cross HS
    : Dietary calcium and growth modulation of human colon cancer cells: role of the extracellular calcium-sensing receptor. Cancer Detect Prev 24: 127-136, 2000.
    OpenUrlPubMed
  89. 89.↵
    1. Sheinin Y,
    2. Kállay E,
    3. Wrba F,
    4. Kriwanek S,
    5. Peterlik M,
    6. Cross HS
    : Immunocytochemical localization of the extracellular calcium-sensing receptor in normal and malignant human large intestinal mucosa. J Histochem Cytochem 48: 595-602, 2000.
    OpenUrlAbstract/FREE Full Text
  90. 90.↵
    1. MacLeod RJ,
    2. Hayes M,
    3. Pacheco I
    : Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells. Am J Physiol Gastrointest Liver Physiol 293: G403-411, 2007.
    OpenUrlAbstract/FREE Full Text
  91. 91.↵
    1. Palmer HG,
    2. Gonzalez-Sancho JM,
    3. Espada J,
    4. Berciano MT,
    5. Puig I,
    6. Baulida J,
    7. Quintanilla M,
    8. Cano A,
    9. de Herreros AG,
    10. Lafarga M,
    11. Muñoz A
    : Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 154: 369-387, 2001.
    OpenUrlAbstract/FREE Full Text
  92. 92.↵
    1. Nittke T,
    2. Selig S,
    3. Kállay E,
    4. Cross HS
    : Nutritional calcium modulates colonic expression of vitamin D receptor and pregnane X receptor target genes. Mol Nutr Food Res 52: 45-51, 2008.
    OpenUrl
  93. 93.↵
    1. Canaff L,
    2. Hendy GN
    : Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem 277: 30337-3035, 2002.
    OpenUrlAbstract/FREE Full Text
  94. 94.↵
    1. Colston KW,
    2. Berger U,
    3. Coombes RC
    : Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet 1: 188-191, 1989.
    OpenUrlPubMed
  95. 95.
    1. Garland FC,
    2. Garland CF,
    3. Gorham ED,
    4. Young JF
    : Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19: 614-622, 1990.
    OpenUrlCrossRefPubMed
  96. 97.
    1. Lipkin M,
    2. Newmark HL
    : Vitamin D, calcium and prevention of breast cancer: a review. J Am Coll Nutr 18: 392S-7S, 1999.
    OpenUrlCrossRefPubMed
  97. 97.
    1. Grant WB
    : An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 94: 1867-75, 2002.
    OpenUrlCrossRefPubMed
  98. 98.
    1. Grant WB
    : Ecologic studies of solar UV-B radiation and cancer mortality rates. Recent Results Cancer Res 164: 371-377, 2003.
    OpenUrlPubMed
  99. 99.↵
    1. Grant WB
    : An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Cancer 94: 272-281, 2002.
    OpenUrlCrossRefPubMed
  100. 100.↵
    1. Colston KW,
    2. Hansen CM
    : Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer 9: 45-59, 2002.
    OpenUrlAbstract
  101. 101.↵
    1. Mathiasen IS,
    2. Sergeev IN,
    3. Bastholm L,
    4. Elling F,
    5. Norman AW,
    6. Jaattela M
    : Calcium and calpain as key mediators of apoptosis-like death induced by vitamin D compounds in breast cancer cells. J Biol Chem 277: 30738-30745, 2002.
    OpenUrlAbstract/FREE Full Text
  102. 102.↵
    1. Almquist M,
    2. Manjer J,
    3. Bondeson L,
    4. Bondeson AG
    : Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women. Cancer Causes Control 18: 595-602, 2007.
    OpenUrlCrossRefPubMed
  103. 103.↵
    1. El Hiani Y,
    2. Ahidouch A,
    3. Roudbaraki M,
    4. Guenin S,
    5. Brule G,
    6. Ouadid-Ahidouch H
    : Calcium-sensing receptor stimulation induces nonselective cation channel activation in breast cancer cells. J Membr Biol 211: 127-137, 2006.
    OpenUrlCrossRefPubMed
  104. 104.↵
    1. Tretli S,
    2. Hernes E,
    3. Berg JP,
    4. Hestvik UE,
    5. Robsahm TE
    : Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 100: 450-454, 2009.
    OpenUrlCrossRefPubMed
  105. 105.↵
    1. Giovannucci E,
    2. Rimm EB,
    3. Wolk A,
    4. Ascherio A,
    5. Stampfer MJ,
    6. Colditz GA,
    7. Willett WC
    : Calcium and fructose intake in relation to risk of prostate cancer. Cancer Res 58: 442-447, 1998.
    OpenUrlAbstract/FREE Full Text
  106. 106.↵
    1. Skinner HG,
    2. Schwartz GG
    : Serum calcium and incident and fatal prostate cancer in the National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 17: 2302-2305, 2008.
    OpenUrlAbstract/FREE Full Text
  107. 107.↵
    1. Skinner HG,
    2. Schwartz GG
    : A prospective study of total and ionized serum calcium and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 18: 575-579, 2009.
    OpenUrlAbstract/FREE Full Text
  108. 108.↵
    1. Leifsson BG,
    2. Ahren B
    : Serum calcium and survival in a large health screening program. J Clin Endocrinol Metab 81: 2149-2153, 1996.
    OpenUrlCrossRefPubMed
  109. 109.↵
    1. Allen NE,
    2. Key TJ,
    3. Appleby PN,
    4. Travis RC,
    5. Roddam AW,
    6. Tjonneland A,
    7. Johnsen NF,
    8. Overvad K,
    9. Linseisen J,
    10. Rohrmann S,
    11. Boeing H,
    12. Pischon T,
    13. Bueno-de-Mesquita HB,
    14. Kiemeney L,
    15. Tagliabue G,
    16. Palli D,
    17. Vineis P,
    18. Tumino R,
    19. Trichopoulou A,
    20. Kassapa C,
    21. Trichopoulos D,
    22. Ardanaz E,
    23. Larrañaga N,
    24. Tormo MJ,
    25. González CA,
    26. Quirós JR,
    27. Sánchez MJ,
    28. Bingham S,
    29. Khaw KT,
    30. Manjer J,
    31. Berglund G,
    32. Stattin P,
    33. Hallmans G,
    34. Slimani N,
    35. Ferrari P,
    36. Rinaldi S,
    37. Riboli E
    : Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 98: 1574-1581, 2008.
    OpenUrlCrossRefPubMed
  110. 110.↵
    1. Hayes RB,
    2. Ziegler RG,
    3. Gridley G,
    4. Swanson C,
    5. Greenberg RS,
    6. Swanson GM,
    7. Schoenberg JB,
    8. Silverman DT,
    9. Brown LM,
    10. Pottern LM,
    11. Liff J,
    12. Schwartz AG,
    13. Fraumeni JF Jr.,
    14. Hoover RN
    : Dietary factors and risks for prostate cancer among blacks and whites in the United States. Cancer Epidemiol Biomarkers Prev 8: 25-34, 1999.
    OpenUrlAbstract/FREE Full Text
  111. 111.↵
    1. Huncharek M,
    2. Muscat J,
    3. Kupelnick B
    : Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60: 421-441, 2008.
    OpenUrlCrossRefPubMed
  112. 112.↵
    1. Yano S,
    2. Macleod RJ,
    3. Chattopadhyay N,
    4. Tfelt-Hansen J,
    5. Kifor O,
    6. Butters RR,
    7. Brown EM
    : Calcium-sensing receptor activation stimulates parathyroid hormone-related protein secretion in prostate cancer cells: role of epidermal growth factor receptor transactivation. Bone 35: 664-672, 2004.
    OpenUrlCrossRefPubMed
  113. 113.↵
    1. Boscoe FP,
    2. Schymura MJ
    : Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer 6: 264, 2006.
    OpenUrlCrossRefPubMed
  114. 114.
    1. Grant WB
    : An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 94: 1867-1875, 2002.
    OpenUrlCrossRefPubMed
  115. 115.↵
    1. Grant WB
    : The likely role of vitamin D from solar ultraviolet-B irradiance in increasing cancer survival. Anticancer Res 26: 2605-2614, 2006.
    OpenUrlAbstract/FREE Full Text
  116. 116.↵
    1. Grau MV,
    2. Baron JA,
    3. Sandler RS,
    4. Haile RW,
    5. Beach ML,
    6. Church TR,
    7. Heber D
    : Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst 95: 1765-177, 2003.
    OpenUrlAbstract/FREE Full Text
  117. 117.↵
    1. Holt PR,
    2. Bresalier RS,
    3. Ma CK,
    4. Liu KF,
    5. Lipkin M,
    6. Byrd JC,
    7. Yang K
    : Calcium plus vitamin D alters preneoplastic features of colorectal adenomas and rectal mucosa. Cancer 106: 287-296, 2006.
    OpenUrlCrossRefPubMed
  118. 118.↵
    1. Fedirko V,
    2. Bostick RM,
    3. Flanders WD,
    4. Long Q,
    5. Shaukat A,
    6. Rutherford RE,
    7. Daniel CR,
    8. Cohen V,
    9. Dash C
    : Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: a randomized, double-blind, placebo-controlled clinical trial. Cancer Prev Res 2: 213-223, 209.
    OpenUrl
  119. 119.↵
    1. Brozek W,
    2. Nittke T,
    3. Kriwanek S,
    4. Bonner E,
    5. Kállay E,
    6. Peterlik M,
    7. Cross HS
    : Mutual associations between age, gender, anatomical location and malignancy of colorectal cancers - relationship to 1,25-dihydroxyvitamin D3 tissue concentrations. Anticancer Res 28: 3223, 2008.
    OpenUrl
  120. 120.↵
    1. Jacobs EJ,
    2. White E,
    3. Weiss NS
    : Exogenous hormones, reproductive history, and colon cancer (Seattle, Washington, USA). Cancer Causes Control 5: 359-366, 1994.
    OpenUrlCrossRefPubMed
  121. 121.↵
    1. Johnson JR,
    2. Lacey JV Jr.,
    3. Lazovich D,
    4. Geller MA,
    5. Schairer C,
    6. Schatzkin A,
    7. Flood A
    : Menopausal hormone therapy and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 18: 196-203, 2009.
    OpenUrlAbstract/FREE Full Text
  122. 122.↵
    1. Martineti V,
    2. Picariello L,
    3. Tognarini I,
    4. Carbonell Sala S,
    5. Gozzini A,
    6. Azzari C,
    7. Mavilia C,
    8. Tanini A,
    9. Falchetti A,
    10. Fiorelli G,
    11. Tonelli F,
    12. Brandi ML
    : ERbeta is a potent inhibitor of cell proliferation in the HCT8 human colon cancer cell line through regulation of cell cycle components. Endocr Relat Cancer 12: 455-469, 2005.
    OpenUrlAbstract/FREE Full Text
  123. 123.↵
    1. Lechner D,
    2. Bajna E,
    3. Adlercreutz H,
    4. Cross HS
    : Genistein and 17β-estradiol, but not equol, regulate vitamin D synthesis in human colon and breast cancer cells. Anticancer Res 26: 2597-2603, 2006.
    OpenUrlAbstract/FREE Full Text
  124. 124.↵
    1. Cross HS,
    2. Kállay E,
    3. Farhan H,
    4. Weiland T,
    5. Manhardt T
    : Regulation of extrarenal vitamin D metabolism as a tool for colon and prostate cancer prevention. Recent Results Cancer Res 164: 413-425, 2003.
    OpenUrlPubMed
  125. 125.↵
    1. Van Cromphaut SJ,
    2. Rummens K,
    3. Stockmans I,
    4. Van Herck E,
    5. Dijcks FA,
    6. Ederveen AG,
    7. Carmeliet P,
    8. Verhaeghe J,
    9. Bouillon R,
    10. Carmeliet G
    : Intestinal calcium transporter genes are up-regulated by estrogens and the reproductive cycle through vitamin D receptor-independent mechanisms. J Bone Miner Res 18: 1725-1736, 2003.
    OpenUrlCrossRefPubMed
  126. 126.↵
    1. Cross HS,
    2. Kállay E,
    3. Lechner D,
    4. Gerdenitsch W,
    5. Adlercreutz H,
    6. Armbrecht HJ
    : Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. J Nutr 134: 1207S-1212S, 2004.
    OpenUrlAbstract/FREE Full Text
  127. 127.↵
    1. Cross HS,
    2. Kállay E
    : Nutritional regulation of extrarenal vitamin D hydroxylase expression - potential application in tumor prevention and therapy. Future Oncol 1: 415-424, 2005.
    OpenUrlCrossRefPubMed
  128. 128.↵
    1. Huncharek M,
    2. Muscat J,
    3. Kupelnick B
    : Colorectal cancer risk and dietary intake of calcium, vitamin D, and dairy products: a meta-analysis of 26,335 cases from 60 observational studies. Nutr Cancer 61: 47-69, 2009.
    OpenUrlCrossRefPubMed
  129. 129.↵
    1. Parodi PW
    : Dairy product consumption and the risk of breast cancer. J Am Coll Nutr 24: 556S-5568S, 2005.
    OpenUrlPubMed
  130. 130.↵
    1. Ghadirian P,
    2. Lynch HT,
    3. Krewski D
    : Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev 27: 87-93, 2003.
    OpenUrlCrossRefPubMed
  131. 131.↵
    1. Chan JM,
    2. Wang F,
    3. Holly EA
    : Pancreatic cancer, animal protein and dietary fat in a population-based study, San Francisco Bay Area, California. Cancer Causes Control 18: 1153-1167, 2007.
    OpenUrlCrossRefPubMed
  132. 132.↵
    1. Grant WB
    : An ecologic study of dietary links to prostate cancer. Altern Med Rev 4: 162-169, 1999.
    OpenUrlPubMed
  133. 133.↵
    1. Ahn J,
    2. Albanes D,
    3. Peters U,
    4. Schatzkin A,
    5. Lim U,
    6. Freedman M,
    7. Chatterjee N,
    8. Andriole GL,
    9. Leitzmann MF,
    10. Hayes RB
    : Dairy products, calcium intake, and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16: 2623-2630, 2007.
    OpenUrlAbstract/FREE Full Text
  134. 134.
    1. Larsson SC,
    2. Berggkvist L,
    3. Wolk A
    : Long-term dietary calcium intake and breast cancer risk in a prospective cohort of women. Am J Clin Nutr 89: 277-282, 2009.
    OpenUrlAbstract/FREE Full Text
  135. 135.
    1. Kesse-Guyot E,
    2. Bertrais S,
    3. Duperray B,
    4. Arnault N,
    5. Bar-Hen A,
    6. Galan P,
    7. Hercberg S
    : Dairy products, calcium and the risk of breast cancer: results of the French SU.VI.MAX prospective study. Ann Nutr Metab 51: 139-145, 207.
    OpenUrl
  136. 136.
    1. Slattery ML,
    2. Sorenson AW,
    3. Ford MH
    : Dietary calcium intake as a mitigating factor in colon cancer. Am J Epidemiol 128: 504-514, 1988.
    OpenUrlAbstract/FREE Full Text
  137. 137.
    1. Yang CY,
    2. Chiu HF,
    3. Chiu JF,
    4. Tsai SS,
    5. Cheng MF
    : Calcium and magnesium in drinking water and risk of death from colon cancer. Jpn J Cancer Res 88: 928-933, 1997.
    OpenUrlCrossRef
  138. 138.
    1. Yang CY,
    2. Chiu HF
    : Calcium and magnesium in drinking water and risk of death from rectal cancer. Int J Cancer 77: 528-532, 1988.
    OpenUrl
  139. 139.
    1. Chiu HF,
    2. Chang CC,
    3. Yang CY
    : Magnesium and calcium in drinking water and risk of death from ovarian cancer. Magnes Res 17: 28-34, 2004.
    OpenUrlPubMed
  140. 140.
    1. Skinner HG,
    2. Michaud DS,
    3. Giovannucci E,
    4. Willett WC,
    5. Colditz GA,
    6. Fuchs CS
    : Vitamin D intake and the risk for pancreatic cancer in two cohort studies. Cancer Epidemiol Biomarkers Prev 15: 1688-1695, 2006.
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top

In this issue

Anticancer Research: 29 (9)
Anticancer Research
Vol. 29, Issue 9
September 2009
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
  • Back Matter (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on Anticancer Research.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Calcium, Vitamin D and Cancer
(Your Name) has sent you a message from Anticancer Research
(Your Name) thought you would like to see the Anticancer Research web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
14 + 2 =
Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.
Citation Tools
Calcium, Vitamin D and Cancer
MEINRAD PETERLIK, WILLIAM B. GRANT, HEIDE S. CROSS
Anticancer Research Sep 2009, 29 (9) 3687-3698;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Reprints and Permissions
Share
Calcium, Vitamin D and Cancer
MEINRAD PETERLIK, WILLIAM B. GRANT, HEIDE S. CROSS
Anticancer Research Sep 2009, 29 (9) 3687-3698;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Relevance of Adequate Calcium Intake for Control of Cellular Growth
    • Relevance of Adequate Plasma Vitamin D Levels for Organ-specific Control of Cell Growth
    • Combined Vitamin D and Calcium Insufficiency
    • Mechanisms of Calcium and Vitamin D Action in Control of Neoplastic Cell Growth
    • Calcium, Vitamin D and Cancer Prevention
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • Association Between Blood Circulating Vitamin D and Colorectal Cancer Risk in Asian Countries: A Systematic Review and Dose-Response Meta-analysis
  • Independent and Joint Associations between Serum Calcium, 25-Hydroxy Vitamin D, and the Risk of Primary Liver Cancer: A Prospective Nested Case-Control Study
  • Association between blood circulating vitamin D and colorectal cancer risk in Asian countries: a systematic review and dose-response meta-analysis
  • Prediagnostic Calcium Intake and Lung Cancer Survival: A Pooled Analysis of 12 Cohort Studies
  • Regulation of VDR Expression in Apc-Mutant Mice, Human Colon Cancers and Adenomas
  • Chemoprevention with Acetylsalicylic Acid, Vitamin D and Calcium Reduces Risk of Carcinogen-induced Lung Tumors
  • Calcium Intake and Lung Cancer Risk Among Female Nonsmokers: A Report from the Shanghai Women's Health Study
  • Epigenetic Differences in Normal Colon Mucosa of Cancer Patients Suggest Altered Dietary Metabolic Pathways
  • Meta-Analyses of Vitamin D Intake, 25-Hydroxyvitamin D Status, Vitamin D Receptor Polymorphisms, and Colorectal Cancer Risk
  • A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on Markers of Their Metabolism in Normal Mucosa of Colorectal Adenoma Patients
  • Vitamin D and Racial Disparities for Pancreatic Cancer - Response
  • A Multicountry Ecological Study of Risk-modifying Factors for Prostate Cancer: Apolipoprotein E {varepsilon}4 as a Risk Factor and Cereals as a Risk Reduction Factor
  • Google Scholar

More in this TOC Section

  • Epidemiology of Vitamin D Insufficiency and Cancer Mortality
  • Modulation of Vitamin D Synthesis and Catabolism in Colorectal Mucosa: A New Target for Cancer Prevention
  • The Dependency of Vitamin D Status on Body Mass Index, Gender, Age and Season
Show more Part B

Similar Articles

Anticancer Research

© 2021 Anticancer Research

Powered by HighWire