ReviewThe potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer
Highlights
► Calcitriol, (active form of vitamin D) exerts anticancer effects in breast cancer models. ► Calcitriol inhibits prostaglandin synthesis and exerts anti-inflammatory effects. ► Calcitriol inhibits estrogen synthesis and signaling and may be beneficial in ER + breast cancer. ► Dietary vitamin D can be converted to calcitriol in the breast and can exert anticancer effects. ► Calcitriol and dietary vitamin D may be useful in breast cancer treatment and chemoprevention.
Introduction
Breast cancer (BCa) is the most common cancer in women [1]. Estrogens drive the proliferation of mammary epithelial cells and therefore promote the growth of estrogen receptor positive (ER+) BCa. Approximately 70% of BCa are ER+ and are responsive to endocrine therapy. The hormonal drugs used to treat ER + BCa are designed to antagonize the mitogenic effects of estrogens and include: selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene that bind to the ER and act as antagonists in the breast; selective estrogen receptor down-regulators (SERDs) such as fulvestrant that bind to and target ER for degradation; and aromatase inhibitors (AIs) that inhibit the activity of aromatase (CYP19A1), the enzyme that catalyzes the synthesis of estrogens from androgenic precursors [2]. Currently AIs are the first line therapy to prevent BCa progression in postmenopausal women following primary therapy [2], [3], [4]. In spite of the available treatments, the incidence of BCa continues to rise and increasing emphasis is being placed on BCa chemoprevention, including approaches to reduce exposure to carcinogens and the use of nutritional agents to prevent and/or delay the development of BCa. This review explores the pathways in cultured cells and animal models that provide strong evidence for the chemopreventive and therapeutic activity of vitamin D in ER + BCa.
Calcitriol, the hormonally active form of vitamin D, (1,25-dihydroxyvitamin D3), plays an important role in calcium homeostasis through its actions in intestine, kidney, parathyroid glands and bone [5]. In recent years it has been recognized that in addition to its actions on calcium and bone homeostasis, calcitriol also exhibits anti-proliferative and pro-differentiation activities indicating its potential use in the prevention and treatment of multiple cancers including BCa [6], [7], [8], [9], [10], [11], [12], [13].
Section snippets
Vitamin D and BCa
Dietary vitamin D3 is not merely a vitamin but the essential precursor to the potent steroid hormone 1,25(OH)2D3 or calcitriol [5], which has anti-proliferative, anti-inflammatory, pro-differentiating and pro-apoptotic activities in many cancers including BCa [8], [10]. Epidemiological studies indicate that vitamin D (no subscript denotes either vitamin D2 or D3) exhibits anticancer activity against BCa and other cancers [8], [10], [14], [15], [16]. Sunlight exposure, which promotes synthesis
Regulation of proliferation, apoptosis, invasion and metastasis
Calcitriol inhibits the growth of both ER + and ER-negative human BCa cell lines [reviewed in [7], [14], [26]]. In general ER + BCa cell lines appear to be more sensitive to the growth inhibitory effects of calcitriol than the ER-negative cell lines [27]. In most BCa cells calcitriol induces cell cycle arrest by increasing the expression of cyclin-dependent kinase inhibitors and decreasing cyclin-dependent kinase activity [28], [29], [30]. In some cells calcitriol promotes apoptosis by modulating
Summary and conclusions
Calcitriol exhibits antiproliferative effects in BCa cell cultures and retards tumor growth in animal models of BCa through a variety of mechanisms. In addition to the many well-known anticancer pathways active in multiple malignant cells, we propose several new mechanisms that are specifically effective in ER + BCa cells. We have identified new calcitriol target genes revealing additional molecular pathways of calcitriol action in BCa. By suppressing the expression of COX-2 and increasing that
Acknowledgement
This work was supported by NCI Grant CA130991 and Komen Foundation Grant 070101 to D.F.
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