Abstract
The association between obesity/overweight and carcinogenesis is a recognized highly complex and still partially unknown process. Nevertheless, these conditions are frequently related with several pathological states such as chronic inflammation, presence of dyslipidemia and insulin-resistance (metabolic disorders) which are now accepted features contributing to the increased hormonal-dependent cancer risk. Breast cancer incidence and outcome is strictly related to metabolic disorders. Thus, managing these emerging risk factors, should be a new and optimal strategy in breast cancer prevention and therapy. Unfortunately, the agents able to interfere with metabolic disorders, produce often light or serious side-effects and consequently their compliance and efficacy are weak. Some nutraceutical compounds seem to be an ideal option with the same activity and effectiveness to ordinary agents but with minor side effects. Berberine, an extraordinary medicinal herb, has been proven to have many clinical pharmacological effects, including lowering of blood glucose, increasing insulin sensitivity, and correcting lipid metabolism disorders. It has a comparable therapeutic effect to common drugs. It acts contemporarily on hyperlipidemia, hyperglycemia and insulin resistance without their related side effects and could be a real alternative in healthy high risk or affected breast cancer patients with metabolic disorders. This commentary examines the pathophysiology of metabolic disorders and its relationship to breast cancer. Moreover, it evaluates the possible role of berberine in the clinical practice.
Cancer is a genetic disease caused by damage in the genome of the cells. Every mutation which occurs at the genomic level is reflected on several pathways generally related to cellular activity. This damage is often acquired throughout life and directly related to a wrong lifestyle (1). The major unhealthy behaviors in developed countries are the tobacco use and dietary/lifestyle factors which taken together they represent more than two-thirds of the acquired risk factors of cancer development. In particular obesity and overweight have become major public health concerns during the last few decades as they are key risk factors for several diseases such as type-2 diabetes, cardiovascular conditions, dyslipidemia, hypertension and some cancers (2). The precise mechanisms that link obesity and cancers remain unclear – particularly in relation to the sequence of events. However, some metabolic changes in the surrounding microenvironment as chronic inflammation state, presence of dyslipidemia and insulin-resistance (generally defined as metabolic disorders) are now substantially accepted features (3) which contribute to increased cancer risk on hormonal-dependent neoplasms, breast cancer included, and a potential target for conventional and nutraceutical therapies.
Metabolic Disorders and Breast Cancer Risk
The association of obesity with cancer and the ongoing obesity epidemic evolution have stimulated several researches in this particular setting. Over the past 40 years the prevalence of obesity and overweight condition has increased epidemically worldwide particularly in developed countries (4). These conditions are recognized risk factors for several diseases but recently a great deal of evidence has suggested that they negatively affect cancer risk and outcome. Growing evidence from epidemiological, preclinical and clinical studies indicates that increased adiposity is associated with increases in cancer incidence and mortality (5). A relative recent meta-analysis and systematic review shows that an increase in the body mass index (BMI) is associated with an enhanced risk of several malignancies and overall with 14% of all cancer deaths in men and with 20% of all cancer deaths in women (6). Recently, the population-attributable fraction (PAF), the proportion of cancers potentially avoidable if the obesity–cancer association is causal, for obesity and cancer risk worldwide has been calculated (7). Approximately 3.6% of all new cancers may be due to high BMI. Interestingly, the PAF in women is more than double than that in men, reflecting the strong relationship between obesity and hormonal cancers such as breast cancer as well. Unfortunately, cancer risk is not only related to obesity or overweight conditions but is also high in presence of metabolic syndrome (MS). MS is characterized by a cluster of endocrine disturbances including mild obesity (particularly central adiposity), glycemic perturbations (particularly the presence of insulin-resistance), raised blood pressure, elevated triglyceride levels and low high-density lipoprotein (HDL) cholesterol levels (8).
Several studies have shown the relationship between these metabolic conditions and the incidence and outcome of mammary neoplasia. A recent case-cohort study on more than 22,000 subjects showed that the presence of metabolic syndrome was associated with significantly increased breast cancer risk in all and in particular in postmenopausal women (HR=1.52, 95%CI=1.14-2.02) and authors suggested that a preventive approach to metabolic syndrome through lifestyle changes could confer protection against breast cancer incidence and prognosis (9). More recently, in a prospective analysis of a cohort of almost 21,000 postmenopausal women, authors found that obese and metabolically unhealthy subjects were associated with the highest risk (HR=1.62; 95%CI=1.33-1.96) of developing cancer and suggested that both obesity and metabolic dysregulation were associated with breast cancer risk. Moreover, beyond BMI, metabolic health should be considered a clinically relevant and modifiable risk factor for breast cancer (10). A complete review of recent literature on these settings identified 11 studies that were published since 2010 (11). It was confirmed that obesity was a risk factor for breast cancer (BC) recurrence and reduced survival. It was also shown that a minor efficacy of treatment with aromatase inhibitors in hormone-receptor positive BC survivors who were obese, in comparison to normal-weight women. In addition, these analyses showed that obesity-induced changes in glucose metabolism, type-2 diabetes, and metabolic syndrome contributed to negative outcomes in BC survivors.
Along with the increasing prevalence of obesity and overweight worldwide, there is an increasing prevalence of type 2 diabetes. Potential interactions between diabetes and breast cancer are complex. Recent research has focused on the effect of this comorbid condition on incidence and mortality in women with breast cancer. The Nurses' Health Study has reported a 17% increased risk of breast cancer incidence (HR=1.17 95%CI=1.01-1.35) in women with diabetes compared with women without this condition. This relationship was predominant in postmenopausal subjects and seemed to be related to estrogen receptor (ER)-positive cancer (12). Not only incidence, but also breast cancer outcome seemed to be related with diabetic and pre-diabetic conditions. A recent authoritative systematic review and meta-analysis examining the effect of pre-existing diabetes on breast cancer–related outcomes has shown that patients with breast cancer and diabetes had a significantly higher all-cause mortality risk (HR=1.49; 95%CI=1.35 to 1.65) compared with their nondiabetic counterparts (13). Authors found also that a pre-existing diabetes condition is associated with a more advanced stage at presentation. Some clinical studies have also examined the association between glycemic control and cancer risk and in a meta-analysis of 14 studies, authors reported an increased risk of breast cancer associated with a HbA1c above 8.5%. (14). Compared with their nondiabetic counterparts, patients with breast cancer and pre-existing diabetes and in general with metabolic disorders involving dislypidemic conditions too, have a greater risk of cancer incidence and death and tend to present at later stages of disease. Thus, we investigated the pathophysiologic interactions between metabolic disorders and breast cancer and determine whether improvements in their care can be beneficial.
The Links Between Metabolic Disorders and Breast Cancer
The relationship between metabolic disorders and breast carcinogenesis is complex and not fully understood. Several pathways related to metabolic abnormalities concur to cancer development and progression, but the importance of each one and the correct sequence of events remains substantially unclear. Fat is recognized as a “real organ” with both metabolic and endocrine functions. Multiple factors like chronic inflammation, insulin-resistance, dyslipidemia and endocrine products associated with abnormal excess and accumulation of fat are certainly related with cancer progression.
There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. The precise physiological events leading to the initiation of an inflammatory response in obesity remains incompletely understood, but a large number of macrophages that comprise up to 40% of resident cells in adipose tissue, remain the main source of pro-inflammatory cytokines such as tumor necrosis factor-(TNF-) and interleukins (IL-6-4-10-12) (15-17). Moreover, the chemokines secreted by adipose tissue macrophages recruit additional leukocytes, thus maintaining and expanding the chronic and subclinical inflammatory process. Chronic inflammation also influences the production (and their ratio) of leptin and adiponectin, two proteins secreted by adipocytes which are inversely related with carcinogenesis. Adiponectin, in contrast to leptin, is in fact inversely associated with obesity and hyperinsulinemia (18) and appears to have anti-inflammatory, anti-angiogenic, proapoptotic and anti-diabetic properties too (19). Moreover, recent evidence demonstrates that the Leptin–Adiponectin (L–A) ratio could be a useful index and surrogate marker of insulin-resistance state (IR) and its associated cancer risk. In accordance with these biological activities, an increased L–A ratio has been associated with risk for several types of cancer including breast.
Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflammatory microenvironment and promote tumor growth. Importantly, adipose inflammation and its pro-tumor consequences, insulin resistance and dyslipidemia in particular can be found in some individuals who are not considered to be obese or overweight by body mass index.
Insulin Resistance
Obesity increases glycemic perturbations and the related cancer risk through induction of insulin resistance. Recently, a new energy-based concept was hypothesized in which insulin resistance is a result of energy surplus in cells and the keys of this relationship are the mitochondrial dysfunction and the reduction of activity of adenosine monophosphate-activated protein kinase (AMPK) (20). Recent evidence suggests that inhibition of the nutrient-sensing enzyme AMPK is an early event in the development of IR in response to high glucose and fatty acids (FA). Practically, presence of obesity or overweight guarantees an ideal substrate to the cells, mainly composed by glucose and fatty acids. In this scenario, there is a mitochondrial over-activation with a surplus of energy production (ATP) that leads to the AMPK signalling pathways inactivation. AMPK is an energy sensor which has also an insulin-sensitizing action on resistant cells and its inactivation by energetic surplus production leads to an insulin resistance state. The complete mechanism that links obesity and IR is summarized in Figure 1.
Moreover, over this insulin-sensitizing action, AMPK has also a direct effect on carcinogenesis. According to several published studies (21), AMPK activation strongly suppresses cell proliferation in both malignant and non-malignant cells. AMPK actions seem to be mediated by multiple mechanisms: on cell cycle progression with activation of p53 suppressor gene and on protein synthesis inhibition by blocking the mTOR pathway.
In obesity, AMPK activity is reduced by the mitochondrial over-activation through energetic substrates. Drugs as metformin or berberine are able to stop the mitochondrial function and restore insulin sensitivity.
Presence of IR is directly and indirectly linked to breast cancer risk and outcome. The direct way is named “insulin-cancer hypothesis” that postulates that the condition of IR has two metabolic consequences both related to cancer disease. The first one involves the insulin–IGF axis and is characterized by the presence of chronic hyperinsulinemia. Insulin is a mutagenic factor which is considered as an independent risk factor for breast cancer and it may have a substantial role in explaining the obesity-breast cancer relationship (22). Generally, its increase is also associated with decreased concentrations of insulin-like growth factor binding protein1 (IGFBP-1) and IGFBP-2, leading to increased availability of IGF-I and by binding to its cellular receptor produces concomitant changes in the cellular environment that favors tumor formation. In contrast, the IR indirect effect on carcinogenesis is related to the presence of hyperglycemia and the metabolic reprogramming which occurs in cancer cells (23). Metabolic shift from catabolic to anabolic metabolism is a classic hallmark of cancer cells. This metabolic reprogramming, known as the Warburg effect (24), results in the use of aerobic glycolysis in preference to oxidative phosphorylation (OXPHOS) for increased energy production in cancer cells. This condition is closely related to glucose availability because cancer cells consume an excessive quantity of glucose, and the presence of hyperglycemia related to IR ensures an ideal microenvironment for cancer cell proliferation and growth. Several clinical studies have confirmed this relationship between IR and cancer incidence. A recent cross-sectional study regarding female cancers, conducted in 121,230 middle-aged and elderly non-diabetic women has shown that the prevalence of both premenopausal and postmenopausal breast cancer, postmenopausal ovarian cancer and premenopausal endometrial cancer was higher in insulin-resistant participants than in insulin-sensitive participants (25). Subgroup analysis revealed that the positive association between insulin resistance and risk of prevalent breast cancer was observed in a population with younger age, overweight or obese, and with impaired glucose tolerance (IGR).
Direct and indirect relationship between cholesterol and hormonal effects.
Thus, suppression of mitochondrial ATP production and activation of AMPK, for example with metformin or with an alternative compound such as berberine (both recognized mitochondrial inhibitors and AMPK activators), could be a promising approach in the treatment of IR and breast cancer related to this condition.
Dyslipidemia
Presence of metabolic disorders including those involved in cholesterol biosynthesis are implicated in cancer development and progression. The accumulation of cholesterol is a general feature of cancer tissue and recent evidence suggests that hypercholesterolemia plays a critical role in the progression of several cancers, breast cancer included (26, 27). Cholesterol is synthesized through the mevalonate pathway, with a series of reactions originally regulated by the HMG-CoA reductase action (28). Studies on cancer cells revealed that cholesterol synthesis is enhanced in comparison with healthy tissue (29) and this suggests the importance of the mevalonate pathway in cancer metabolism and its role as a potential target for therapeutic strategies. In detail, cholesterol is an essential component of breast cell membranes as well as precursor of steroid hormones and the hypothesis that breast cancer cells need excess cholesterol and intermediates of its metabolism, to maintain a high level of proliferation, is substantially accepted.
Endocrine tissues such as the gonads and the adrenals are tissues that are able to produce active steroid hormones from cholesterol and to deliver them into the circulation (30). Steroid hormones have long been recognized as regulators of cell proliferation and differentiation and are intimately associated with the etiology of breast cancer. In addition to these potential direct effects of cholesterol, recent works have identified its primary metabolite, oxysterol, the 27-hydroxycholesterol (27HC) synthesized by the cytochrome P450 oxidase, sterol 27-hydroxylase (CYP27A1), as a further molecule related to carcinogenesis (31). 27 HC can bind to and modulate the activity of both ERα and ERβ and especially on the α-subunit, it is able to increase breast cancer cellular proliferation and tumor growth (32) (Figure 2). In conclusion, high cholesterol levels can stimulate breast cancer development and progression in a double way, increasing steroid hormone production and/or create an active metabolite able to stimulate the estrogen pathway.
Conventional Therapeutic Intervention
The association between insulin-resistance, dyslipidemia and breast cancer development and progression suggests that managing these emerging conditions and their related carcinogenic pathways, should be a new and optimal strategy in breast cancer prevention and therapy. Several studies have also recently examined whether cholesterol-lowering medication (CLM) such as statins and insulin-sensitizing medications (metformin) could be efficacious in this setting (33, 34).
Interestingly, cancer patient's outcome seems to be strictly related to statin or CLM use. Recently, the Breast International Group (BIG) conducted a randomized, phase III, double blinded trial (BIG 1-98) which enrolled more than 8,000 breast cancer postmenopausal women. The trial was designed to answer two questions concerning how best to use endocrine agents for the treatment of early breast cancer in postmenopausal women with hormone receptor-positive tumors. The first was to compare letrozole monotherapy with tamoxifen monotherapy and the second to determine the benefit of letrozole in sequence with tamoxifen (35). In addition to the letrozole superiority, authors also found an important effect related to the patient's metabolic condition. Given the data from previous studies on the mechanism of action of CLM against breast cancer, they hypothesized that CLM in combination with endocrine therapy may improve breast cancer outcome. Three time-to-event endpoints were considered as disease-free survival, breast cancer-free interval and distant recurrence-free interval (36). Interestingly the authors concluded that in 789 patients with breast cancer who used CLM at study baseline had more beneficial tumor characteristics and improved outcomes compared with non-users. The prognostic impact of CLM initiation during endocrine therapy showed beneficial effects of initiating CLM, although the benefit may be restricted to patients who received aromatase inhibitors treatment. Study results suggest that high cholesterol level can reduce the aromatase inhibitors efficacy thus increasing the recurrence rate or in other words the use of CLM during adjuvant therapy may have a role in preventing breast cancer recurrence in ER positive early stage breast cancer.
If statins are the best CLMs, metformin is a biguanide derivative, currently approved for the treatment of non-insulin dependent diabetes mellitus, and an insulin-sensitizing agent with potent antihyperglycemic properties. In the last decades, several studies have shown its anticancer properties on incidence and prognosis of many types of malignancies (37). Researchers suggest that metformin may have different mechanisms of tumor inhibition both via insulin-dependent and independent pathways (38), including activation of AMPK with a consequent inhibition in cancer proliferation and induction of apoptosis (39). An important systematic review and meta-analysis was performed to assess the effect of metformin on cancer incidence and mortality in diabetic patients and suggested that the agent is associated with a decreased risk of cancer incidence (37). In a breast cancer setting another meta-analysis confirmed these data and supported the protective effect of metformin on breast cancer risk among postmenopausal women with diabetes (40). In non-diabetic subjects, a recent pre-surgical trial evaluated changes in Ki-67 between pre-treatment biopsy and post-treatment surgical specimens and indicated that Ki-67 had a prognostic value and might predict antitumor activity in breast cancer (41). The research showed that metformin administered before surgery did not significantly reduce Ki-67 overall but had a significantly opposite effect depending on IR, particularly on luminal B tumors. There was a proportional decrease in Ki-67 of 10.5% in women with a homeostasis model assessment (HOMA-index) score >2.8, while an opposite increase of 11.1% was observed in women with a HOMA score <2.8. Interestingly, similar drug effects on Ki-67 were noted to be related to BMI, waist/hip ratio, alcohol consumption and C-reactive protein (CRP). Moreover, an overall reduction in CRP and total cholesterol were noted in the metformin group. These findings confirm that metabolic disorders directly influence cancer risk and outcome, and so these disorders should be treated to combat cancer.
Unfortunately, the agents that have already demonstrated their ability to interfere with metabolic disorders, are limited in their clinical use. They can produce light or serious side effects with consequent weak compliance and efficacy (Figure 3). Moreover, patients often refuse a statin or metformin treatment for a long time period because they perceive it as an overtreatment especially in case of an ongoing adjuvant treatment (i.e. aromatase inhibitors). For these reasons, we urgently need to find alternative/synergistic compounds with similar activity and effectiveness but with fewer or no side effects. Recently, several researchers have directed their attention on nutraceutical compounds, which seem to be safe and effective to modulate metabolic disorders and give us an authoritative clinical alternative.
Berberine
Berberine (BBR) is a quaternary ammonium salt from the protoberberine group, highly concentrated in the roots, rhizomes and stem bark of various plants as Berberis gender. BBR has been used since a very long time in clinical practice as a luminally acting agent with different anti-diarrheal mechanisms including bactericidal activity (42). As reported below, a great number of reports demonstrated the effectiveness of BBR supplementation in lipid disorders and hyperglycemia. The major disadvantage of BBR is its poor oral bioavailability which is attributed mainly to a P-glycoprotein (P-gp)-mediated gut extrusion process (43). This limit has been overcome with its combination with a potent P-gp inhibitor such as silymarin (from Silybum marianum) (44). A combination of BBR and silymarin has shown greater biodisponsibility and consequently good clinical effectiveness in reducing cholesterol and glycaemia than BBR extract alone (45). BBR has been shown to regulate both glucose and lipid metabolism in vitro and in vivo, and so could be administered alone or together with other nutraceuticals or conventional drugs to manage metabolic disorders associated with increased cancer risk and progression.
Metformin and statins' side effects.
Several mechanisms of action are involved in its dual ability on modulating a lipid and glycemic profile. Adequate evidences supports the potential role of BBR as an antidiabetic agent mainly due to its action on AMPK signaling pathway (activator) with subsequent reduction of insulin-resistance state and induction of glycolysis (46). In detail, in the glycemic setting, BBR has demonstrated its effectiveness in diabetic patients, significantly decreasing fasting and postprandial blood glucose and glycosylated haemoglobin (HbA1c) levels (47, 48). BBR regulates glucose metabolism by stimulating glucose uptake by glucose transporter type 4 (GLUT-4) up-regulation (49) and activating 5’ adenosine monophosphate-activated protein kinase (5’ AMPK) because of inhibition of mitochondrial function (50). Interestingly, these different mechanisms mean BBR can be combined with other glucose-lowering agents (51) in order to increase efficacy without increasing side effects.
In addition, BBR acts on lipid profile principally increasing expression of the hepatic LDL receptor (LDLR). BBR can increase the available receptors by the inhibition of Pro-protein-Convertase-subtilisin-Kexin-9 (PCSK9) (52). These mechanisms are distinct from those recognized by statins therapy, which instead decrease cholesterol biosynthesis through HMG-CoA reductase inhibition (53). Moreover, the cholesterol-lowering action of BBR could be increased by adding monacolins, which are naturally derived statins and are relatively safe compounds derived from Monascus purpureus/Red Yeast Rice (RYR) fermentation (54). Recently, RYR has been formulated together with berberine from B. aristata (55). This association is thought to generate a pharmacodynamic synergy due to the opposing effects exerted by berberine and monacolins on PCSK9 and HMG-CoA reductase (Figure 4).
Several randomized studies have confirmed the efficacy of BBR on glycemic and lipidemic pathways modulation. A systemic review and meta-analysis of RCTs showed that BBR was effective in treating hyperglycemia, demonstrating significant reductions in several glycemic parameters such as fasting plasma glucose levels (FPG), postprandial plasma glucose levels (PPG) and HbA1c (48). Moreover, compared to oral hypoglycemic drugs alone, BBR administered with the same oral hypoglycemics showed a better glycemic control. No serious adverse effects from BBR were reported (51). Another meta-analysis of about twenty-seven randomized controlled clinical trials including more than 2,500 patients indicated that BBR has comparable therapeutic effects on type 2DM, hyperlipidemia and hypertension with no serious side effects (56). Considering the relatively low cost compared to other first-line medicines and treatments, BBR might be a good alternative for low socioeconomic status patients to treat type 2DM, hyperlipidemia, and hypertension over a long time period.
In the lipid profile, data are equally consistent. A recent systemic review and meta-analysis of RCTs showed that administration of BBR produced a significant reduction in the levels of total cholesterol (−25%), triglycerides (−20%) and low-density lipoprotein cholesterol (−30%), with a remarkable increase in HDL (47). In monotherapy, BBR in more than one hundred euglycemic, overweight dyslipidemic patients showed to be a safe and effective compound in improving the lipid profile, insulin-resistance state and adipocytokines levels (57). In addition, in 136 obese and T2DM subjects it showed the ability to ameliorate lipid and glycemic profiles, visceral adiposity and blood pressure parameters (58). The different mechanisms of action compared to statins, lead to the possibility to increase the efficacy of BBR which can be used as an add-on therapy condition too. Kong et al. in 2008 (59) suggested that a combination therapy for hyperlipidemia using BBR and simvastatin, could be a new regimen for hypercholesterolemia. Furthermore, add-on therapy regimen seems to be a good alternative in order to control statins side effects. A recent study (60) suggests the possibility to give half of the previously taken dose of statins, in patients intolerant to conventional doses, in addition to BBR, without decreasing the efficacy. Finally, research has been done to evaluate effectiveness of BBR plus monacolins, formulation. The effects of a cholesterol-lowering supplement containing berberine, silymarin, and MK-20 (BSM) in patients with dyslipidemia were clinically analyzed in a recent authoritative Italian work (61). In particular, the clinical role of BSM in naïve and in statin-intolerant patients was retrospectively evaluated and the effects observed were compared with those obtained in patients without treatment or treated with lovastatin. Total cholesterol, low density lipoprotein, and triglyceride levels were lower, and the creatine phosphokinase increase was reduced in patients treated with BSM compared to those treated with lovastatin. Similar results were also obtained in statin-intolerant subjects where BSM was administered as add-on therapy to other compounds such as ezetimibe or fenofibrate. Authors concluded that BSM was a food supplement potentially useful 1) as a primary intervention in subjects with dyslipidemia 2) as add-on therapy in mildly statin-intolerant patients; and 3) in dyslipidemic patients with a negative perception of statins who preferred a treatment seen as natural.
Berberine's mechanisms of action.
Conclusion
Metabolic disorders define a series of alterations involved in both lipid and glycemic profiles and by now they are recognized risk factors for the incidence and outcome of several kinds of cancer in particular -but not only- those that are hormone-dependent, such as breast cancer. The mechanisms which link metabolic disorders and cancer are complex and not fully understood, but certainly driven by the presence of insulin-resistance, dyslipidemia and inflammatory state. The agents able to interfere with these pathways have both light and serious side-effects. For these reasons, we need to find alternative and/or synergistic agents safer than these. A natural compound like BBR, has abundantly shown in mono and in add-on therapy profiles, its ability to modulate these pathways without limiting side-effects and could be a safe and valid alternative to conventional drugs in breast cancer prevention and therapy.
The authoritative and abundant data present in the literature have pushed important Italian and European societies on cardiovascular and diabetic diseases, to insert BBR in their joint position statement and guidelines in order to accept and advise the use of BBR in selected patients (62, 63). We suggest it is time to consider this approach in cancer and in a breast cancer setting too.
- Received June 5, 2018.
- Revision received June 18, 2018.
- Accepted June 19, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
