Vitamin D and the mammary gland: a review on its role in normal development and breast cancer
Breast Cancer Research volume 14, Article number: 211 (2012)
Breast cancer is a heterogeneous disease associated with diverse biological behaviours and clinical outcome. Although some molecular subgroups of breast cancer have a targeted therapy, the most aggressive tumours still lack a molecular target. Despite vitamin D being classically associated with the physiological role of calcium regulation and phosphate transport in bone metabolism, several studies have demonstrated a wide range of functions for this hormone, which are particularly important in the field of cancer. The mechanisms underlying the protective actions of vitamin D in cancer development are only sparsely understood, but evidence shows that vitamin D participates in cell growth regulation, apoptosis and cell differentiation. In addition, it has been implicated in the suppression of cancer cell invasion, angiogenesis and metastasis. Most of vitamin D biological actions are mediated by the vitamin D receptor and the synthesis and catabolism of this hormone are regulated by the enzymes CYP27B1 and CYP24A1. In the present review we highlight research data concerning the function of this hormone in the mammary gland, with a special focus on breast carcinogenesis. Hence, and although the available data are controversial, we consider not only updated information on the epidemiology of vitamin D in breast cancer and its potential value as a therapeutic agent or prophylactic (with an emphasis on molecular mechanisms and effectors of vitamin D action), but include data on its role in other stages of breast cancer progression as well. Accordingly, we review data on the influence of vitamin D in the development of normal breast and the expression of vitamin D-related proteins (VDR, CYP27B1 and CYP24A21) in benign mammary lesions and ductal carcinomas in situ.
Vitamin D was first identified in 1919 by Edward Mellanby as a lipid soluble substance with anti-rachitic properties and is classically associated with its physiological role of calcium and phosphate regulation in bone metabolism. Humans can obtain vitamin D from two main sources: from the diet and from sunlight exposure. Few natural foods contain vitamin D in significant amounts; among these, fatty fish, eggs and sun-dried mushrooms can be highlighted. Still, the majority (90 to 95%) of the required vitamin D is produced by the skin when exposed to sunlight (ultraviolet B radiation) , which has caused vitamin D to be nicknamed 'the sunshine vitamin'. The biologically active form of vitamin D (1α,25- dihydroxy-vitamin D3 or 1α,25(OH)2D3) is synthesised in the kidney by the mitochondrial enzyme CYP27B1 . In order to maintain the homeostasis of the organism, especially regarding the levels of calcium and phosphate, the amount of circulating vitamin D has to be tightly regulated. The enzyme CYP24A1 plays a key role in this process, and is activated by 1α,25(OH)2D3 whenever there is an increase in the levels of this hormone. This enzyme is responsible for converting 1α,25(OH)2D3 to biologically inactive metabolites . In this review, for simplicity purposes, whenever we state vitamin D, we are referring to the biologically active form (1α,25(OH)2D3) unless stated otherwise.
Vitamin D is a steroid hormone that exerts most of its biological activities by binding to a specific high-affinity receptor, the vitamin D receptor (VDR). VDR belongs to the superfamily of nuclear receptors for steroid hormones and regulates gene expression by acting as a ligand-activated transcription factor . However, vitamin D can also induce VDR-independent effects, indicated by the fact that the anti-proliferative effects of vitamin D in MCF-7 cells are not exclusively dependent on the presence of the VDR . Vitamin D is also known to exert rapid effects that are not dependent on gene transcription . Presumably, these effects are mediated by cell surface membrane receptors. Two proteins have been implicated in expression-independent vitamin D action: membrane VDR and the membrane-associated rapid response steroid binding (1,25D3-MARRS) protein. The evidence for the existence of a vitamin D membrane receptor came from two observations: first, the existence of vitamin D analogues that can cause rapid actions of vitamin D, but show low levels of affinity to the VDR [6, 7]; and second, the existence of a vitamin D binding protein that has been described in the basolateral membrane of rat and chick enterocytes . Besides the role of 1,25D3-MARRS as a vitamin D binding protein, the VDR can mediate non-transcriptional effects . The most striking evidence supporting this hypothesis was the demonstration that the vitamin D-induced rapid actions are lost in osteoblasts from Vdr knockout mice . Moreover, VDR has been identified within caveolae-enriched plasma membrane fractions from various cell types , suggesting that it can also work as a membrane receptor.
The role of vitamin D in health and disease is far from understood and the literature is full of contradictory findings. The role of vitamin D in cancer is particularly controversial. Still, evidence that vitamin D is capable of modulating several features of cancer exist. Anti-carcinogenic properties of this hormone include the inhibition of cell proliferation, invasion, metastasis and angiogenesis, and the induction of apoptosis and differentiation . These issues will be further elaborated on in the light of breast cancer development in the following sections and controversial issues discussed.
Vitamin D in breast carcinogenesis
Epidemiology of vitamin D in breast cancer
There has been a great amount of information in the literature regarding a protective role of vitamin D in breast cancer. Two major types of epidemiological studies have been conducted: first, those that focused on the association between solar radiation and breast cancer risk; and second, those that analysed the relationship between vitamin D intake and breast cancer risk.
The first set of epidemiological studies demonstrated that decreased sunlight exposure, and consequent diminished vitamin D production by the skin, was correlated with higher breast cancer incidence and mortality . One study described that women with breast cancer had, on average, lower vitamin D blood levels than women without breast cancer , hence proposing a potential protective effect of vitamin D. In line with this observation, early stage breast cancer patients show higher serum levels of vitamin D than those who have advanced bone metastatic disease and these changes in hormonal levels preceded clinical signs of progression and predicted disease response . Additional evidence is provided by an inverse association between the circulating levels of 25-hydroxyvitamin D3 (the inactive circulating form of vitamin D, which is used to measure the levels of vitamin D in the blood stream) and the risk for developing breast cancer, suggesting that high levels of 25-hydroxyvitamin D3 may be associated with a reduced risk of breast cancer . Furthermore, it has been described that patients with the most aggressive type of breast cancer (triple-negative and basal-like) display the lowest levels of 25-hydroxyvitamin D3 [15, 16]. These results are supported by a recent study where it was observed that breast cancer patients with suboptimal vitamin D levels are more likely to have tumours with aggressive profiles and worse prognostic markers . Hence, these reports indicate that vitamin D deficiency may be linked with increased breast cancer risk, as well as with the development of more aggressive carcinomas. In contrast, other studies found no associations of vitamin D plasma levels or intake with reductions in breast cancer risk. For example, it has been reported that supplementation with calcium and vitamin D did not reduce invasive breast cancer incidence [18, 19]. In line with this, it has been observed that circulating levels of vitamin D were not significantly associated with breast cancer risk [19–21].
Although some of these studies demonstrate a potential protective role for vitamin D in breast cancer, suggesting that disruption of the vitamin D signalling pathway may be a predisposition to develop the disease, others have failed to support a causal relationship between vitamin D intake or supplementation and breast cancer risk. Thus, further studies are required in order to clarify this issue.
Role of vitamin D in normal breast development
The VDR is expressed in the normal mammary gland and vitamin D has been shown to play an important role in the development and function of the mammary gland. Most studies conducted to elucidate the role of vitamin D in breast development have been based on the use of Vdr knockout mice. Zinser and colleagues  performed an elegant study on the role of the vitamin D signalling pathway in the growth regulation of the mammary gland during pubertal development. They showed that Vdr knockout female mice display more extensive ductal elongation and branching when compared with their wild-type counterparts. Furthermore, they observed that this enhanced morphogenesis was not associated with the deregulation of cell proliferation and apoptosis pathways in terminal end buds . Moreover, they saw that VDR ablation leads to an increase of breast responsiveness to exogenous hormones (oestrogen and progesterone), represented by an increase in cell growth . Collectively, these data indicate that VDR could have an important impact on breast development and suggest that the vitamin D signalling pathway participates in the negative growth regulation of the mammary gland. In another study published by the same group , it was shown that Vdr knockout mice had delayed mammary gland regression after weaning and that this effect was associated with reduced apoptosis in the epithelial cell compartment, hence highlighting the contribution of VDR to mammary gland biology during the reproductive cycle.
Immunohistochemical studies on human material have demonstrated that the VDR protein is expressed in samples from normal breast tissues [25, 26]. However, there are some discrepancies concerning the expression of the main enzymes involved in vitamin D metabolism (CYP27B1 and CYP24A1) in normal breast, probably due to the use of different methodologies. Studies assessing the mRNA of the two genes confirmed their expression in the normal mammary gland [27–30] and demonstrated that both enzymes are functionally active in normal breast . In contrast, our group showed, by immunohistochemistry, that both enzymes are detectable in normal breast, but not in all cases . In fact, although the majority of the cases (over 60%) presented CYP27B1 expression, only a small percentage (about 30%) of these presented detectable CYP24A1 protein expression (Figure 1). This work provided evidence for an imbalance in the enzymes that favours the presence of vitamin D in the normal mammary gland. Together with the fact that VDR has an important impact on breast development, it supports the role of the vitamin D signalling pathway in the growth and developmental control of the mammary gland.
Vitamin D in benign lesions of the mammary gland
Benign lesions of the breast can be associated with distinct clinical behaviours and their accurate classification is applicable to patient management in terms of surgical treatment and prophylaxis . In contrast to the extensive studies addressing the expression of Vitamin D signalling and metabolic pathways in breast cancer, the studies in benign lesions of the mammary gland have been ignored. Recently, we have evaluated the expression of VDR, CYP27B1 and CYP24A1 in a series of breast benign lesions . This series consisted of usual and atypical ductal hyperplasias, columnar cell lesions, papillomatosis and adenosis. The results we obtained indicate that the most benign lesions express VDR and CYP27B1 and less than 20% of these cases detectably express CYP24A1. Decreased levels of the three proteins was observed in benign lesions when compared with normal breast, although the results were not statistically significant. This observation may indicate a disturbance in the levels of the proteins that regulate vitamin D metabolism and signalling in early stages of breast cancer development (Figure 1).
Vitamin D in breast cancer models
Suppression of cell growth by vitamin D paved the way for vitamin D to be considered as a potential therapy in cancer research. Since then, numerous studies have been conducted in various cancer models in order to identify the signalling pathways and molecular mediators associated with such effects and these have shown the ability of vitamin D to affect different features of cancer (Figure 2). It was convincingly demonstrated in many of these studies that vitamin D has a prominent role in tumour cell proliferation, and cell cycle genes have consequently become the centre of attention to decrypt the molecular mechanisms of vitamin D in cancer.
Treatment of breast cancer cell lines with vitamin D elicits a change in the expression of proteins involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDKs) and CDK inhibitors . Vitamin D and analogues induce increased expression of the CDK inhibitors p21 and p27, thus blocking cell cycle progression [32–34]. Concomitantly, treatment with this hormone leads to impaired expression and activity of CDK2, CDK4, cyclin D1, cyclin D3, cyclin A1 and cyclin E1, which provoked cell cycle arrest at the G0-G1 transition [32–34], and this effect was correlated with hypophosphorylation of the retinoblastoma protein pRB. Together with these effects on cell cycle proteins, a downregulation of c-Myc oncoprotein was reported, further contributing to the inhibition of cell proliferation . Altogether, these results demonstrate that vitamin D hampers proliferation by targeting several key masters of cell cycle progression. Additionally, it has been proposed that the transcription factor CCAAT enhancer binding protein alpha (C/EBPα) may mediate vitamin D growth inhibitory effects, since C/EBPα is induced by the treatment with vitamin D. A decrease in cell proliferation was observed in C/EBPα-negative MDA-MB-231 cells transfected with C/EBPα, while the knockdown of C/EBPα suppressed the antiproliferative effects of vitamin D in MCF-7 cells, thus providing evidence for the involvement of this transcription factor in breast cancer proliferation . The breast cancer tumour suppressor TCF-4 is another molecular target of vitamin D action, as it has been reported that this transcriptional regulator is present at lower levels in Vdr knockout mice, which suggests a role for TCF-4 in the antiproliferative effects induced by vitamin D . Furthermore, vitamin D induction of the BRCA1 gene (Breast cancer 1) has also been inversely correlated with cell proliferation , while it has been described that vitamin D decreases aromatase expression  and, thus, can modulate oestrogen receptor-positive breast cancer growth.
Together with growth arrest, vitamin D has a role in the induction of apoptosis in breast cancer cells (Figure 2), since cell shrinkage, chromatin condensation and DNA fragmentation are observed in MCF-7 cells treated with this hormone . The most probable mechanism of such vitamin D-induced apoptosis is through the downregulation of the anti-apoptotic protein Bcl-2 . Vitamin D is able to enhance tumour necrosis factor alpha through caspase-dependent (increased caspase 3 activity) and caspase-independent mechanisms . In support of the role of caspase-independent cell death mediated by vitamin D, it was shown that induction of apoptosis in MCF-7 cells was correlated with disruption of mitochondrial function, which was associated with Bax translocation from the cytosol to the mitochondria, cytochrome C release and production of reactive oxygen species. These mitochondrial effects did not require caspase activation, since these were not blocked by a specific caspase inhibitor . Another caspase-independent cell death mechanism induced by vitamin D relies upon cytosolic calcium accumulation associated with an increase in lysosomal protease activity . Finally, vitamin D was still described as a prooxidant in breast cancer cells, causing an increase in the overall cellular redox potential , which may also be an important mechanism underlying the pro-apoptotic effects of this hormone. Vitamin D is able to potentiate and enhance the morphological effects of apoptosis when administered to MCF-7 cells in combination with tamoxifen . Effects of other anticancer agents are improved by the administration of vitamin D: it has been reported that pre-treatment of breast cancer cells with vitamin D enhances the cytotoxicity of doxorubicin , lowers the threshold for taxol-induced cell death  and enhances the growth inhibition effect induced by cisplatin in MCF-7 cells . Importantly, a recent study demonstrates that the interaction between p53 and VDR provides a mechanism for mutant p53 (the most common genetic alteration in human cancers) gain-of-function. This may have clinical implications and suggests that p53 status should be considered when studying vitamin D for cancer therapy .
Vitamin D plays an important role in the modulation of cancer invasion and metastasis as well (Figure 2). Hansen and collaborators  demonstrated that vitamin D has the ability to inhibit the invasive potential of human breast cancer cells in vitro. This reduced invasiveness was found to be associated with diminished activity of the metalloproteinase MMP-9 and downregulation of the plasminogen-activator, simultaneously with increased tissue inhibitor of MMP-1 activity and the induction of plasminogen-activator inhibitor . This is indicative of the dual effect of vitamin D in the invasive process: on one hand, it decreases the activity and expression of metalloproteinases and serine proteases; at the same time, it induces their inhibitors. In vitro experiments using vitamin D analogues have demonstrated that they can inhibit the invasive potential of mammary cancer cells , as well as prevent skeletal metastasis and prolong survival time in nude mice transplanted with human breast cancer cells . This is in line with the observation that vitamin D induces cell adhesion as well as impairs in vitro motility , hence contributing to a less aggressive phenotype in breast cancer cell lines. Furthermore, vitamin D is able to downregulate the expression of P-cadherin , an invasion promoter molecule in breast cancer cells . We have addressed the effects of vitamin D in E-cadherin-negative breast cancer cell lines and have observed that treatment with vitamin D induces the de novo expression of E-cadherin in MDA-MB-231 cells by CDH1 promoter demethylation , providing further evidence for a vitamin D role in invasion and metastasis.
Angiogenesis is yet another cancer feature that vitamin D can modulate (Figure 2). An analogue of vitamin D was able to inhibit angiogenesis at low concentrations in vivo . Using xenografted mice with vascular endothelial growth factor (VEGF)-overexpressing MCF-7 breast cancer cells, it was demonstrated that the administration of vitamin D results in reduced vascularisation of tumours . The tumours formed in the treated animals displayed smaller capillaries when compared with their littermates, suggesting that vitamin D may also inhibit vessel growth and maturation. Additional evidence for angiogenesis inhibition by vitamin D and analogues has shown that it occurs through a decrease in VEGF and tenascin-C expression [59, 60].
The anti-proliferative, pro-apoptotic, anti-invasion and anti-angiogenic properties of vitamin D indicate that it could serve as a potential therapeutic agent. However, breast cancer is not one disease and is divided into many different molecular subtypes . This may partly explain the many different functions described above for vitamin D. In order to transform vitamin D into a (targeted) therapy, a better understanding of the role and function of this hormone in solid tumours is required, accompanied by an upfront stratification of the different patient cohorts in the vitamin D research field.
The data described provide evidence for an essential role of vitamin D in normal development of the mammary gland and breast cancer. Epidemiological studies are conflicting and their results not consistent, with the current view indicating no protective role for vitamin D in breast cancer development. Still, the different functions and effects of vitamin D on cancer cell biology, such as the cell cycle, apoptosis, invasion and metastasis, as well as angiogenesis, virtually bring together the entire spectrum of tumour development under its purview.
CCAAT enhancer binding protein alpha
cyclin dependent kinase
membrane-associated rapid response steroid binding
vitamin D receptor
vascular endothelial growth factor.
Holick MF: Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004, 80: 1678S-1688S.
Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, Dominguez CE, Jurutka PW: The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res. 1998, 13: 325-349.
Evans RM: The steroid and thyroid hormone receptor superfamily. Science. 1988, 240: 889-895.
Costa JL, Eijk PP, van de Wiel MA, ten Berge D, Schmitt F, Narvaez CJ, Welsh J, Ylstra B: Anti-proliferative action of vitamin D in MCF7 is still active after siRNA-VDR knock-down. BMC Genomics. 2009, 10: 499-
Deeb KK, Trump DL, Johnson CS: Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 2007, 7: 684-700.
Dormanen MC, Bishop JE, Hammond MW, Okamura WH, Nemere I, Norman AW: Nonnuclear effects of the steroid hormone 1 alpha,25(OH)2-vitamin D3: analogs are able to functionally differentiate between nuclear and membrane receptors. Biochem Biophys Res Commun. 1994, 201: 394-401.
Norman AW, Bouillon R, Farach-Carson MC, Bishop JE, Zhou LX, Nemere I, Zhao J, Muralidharan KR, Okamura WH: Demonstration that 1 beta,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1 alpha,25-dihydroxyvitamin D3. J Biol Chem. 1993, 268: 20022-20030.
Nemere I, Dormanen MC, Hammond MW, Okamura WH, Norman AW: Identification of a specific binding protein for 1 alpha,25-dihydroxyvitamin D3 in basal-lateral membranes of chick intestinal epithelium and relationship to transcaltachia. J Biol Chem. 1994, 269: 23750-23756.
Zanello LP, Norman AW: Rapid modulation of osteoblast ion channel responses by 1alpha,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. Proc Natl Acad Sci USA. 2004, 101: 1589-1594.
Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW: The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol. 2004, 18: 2660-2671.
van der Rhee H, Coebergh JW, de Vries E: Sunlight, vitamin D and the prevention of cancer: a systematic review of epidemiological studies. Eur J Cancer Prev. 2009, 18: 458-75.
Janowsky EC, Lester GE, Weinberg CR, Millikan RC, Schildkraut JM, Garrett PA, Hulka BS: Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk. Public Health Nutr. 1999, 2: 283-291.
Mawer EB, Walls J, Howell A, Davies M, Ratcliffe WA, Bundred NJ: Serum 1,25-dihydroxyvitamin D may be related inversely to disease activity in breast cancer patients with bone metastases. J Clin Endocrinol Metab. 1997, 82: 118-122.
Bertone-Johnson ER, Chen WY, Holick MF, Hollis BW, Colditz GA, Willett WC, Hankinson SE: Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2005, 14: 1991-1997.
Peppone LJ, Rickles AS, Janelsins MC, Insalaco MR, Skinner KA: The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. Ann Surg Oncol. 2012
Rainville C, Khan Y, Tisman G: Triple negative breast cancer patients presenting with low serum vitamin D levels: a case series. Cases J. 2009, 2: 8390-
Peppone L, Rickles A, Huston A, Sprod L, Hicks D, Mustian K, Skinner K: The association between prognostic demographic and tumor characteristics of breast carcinomas with serum 25-OH vitamin D levels. Cancer Epidemiol Biomarkers Prev. 2011, 20: 717-
Anderson LN, Cotterchio M, Vieth R, Knight JA: Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. Am J Clin Nutr. 2010, 91: 1699-1707.
Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, Rossouw J, Lane D, O'Sullivan MJ, Yasmeen S, Hiatt RA, Shikany JM, Vitolins M, Khandekar J, Hubbell FA, Women's Health Initiative Investigators: Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst. 2008, 100: 1581-1591.
Eliassen AH, Spiegelman D, Hollis BW, Horst RL, Willett WC, Hankinson SE: Plasma 25-hydroxyvitamin D and risk of breast cancer in the Nurses' Health Study II. Breast Cancer Res. 2011, 13: R50-
McCullough ML, Stevens VL, Patel R, Jacobs EJ, Bain EB, Horst RL, Gapstur SM, Thun MJ, Calle EE: Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort. Breast Cancer Res. 2009, 11: R64-
Zinser GM, Sundberg JP, Welsh J: Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis. 2002, 23: 2103-2109.
Zinser G, Packman K, Welsh J: Vitamin D(3) receptor ablation alters mammary gland morphogenesis. Development. 2002, 129: 3067-3076.
Zinser GM, Welsh J: Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice. Mol Endocrinol. 2004, 18: 2208-2223.
Berger U, Wilson P, McClelland RA, Colston K, Haussler MR, Pike JW, Coombes RC: Immunocytochemical detection of 1,25-dihydroxyvitamin D receptors in normal human tissues. J Clin Endocrinol Metab. 1988, 67: 607-613.
Lopes N, Sousa B, Martins D, Gomes M, Vieira D, Veronese LA, Milanezi F, Paredes J, Costa JL, Schmitt F: Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions. BMC Cancer. 2010, 10: 483-
de Lyra EC, da Silva IA, Katayama ML, Brentani MM, Nonogaki S, Goes JC, Folgueira MA: 25(OH)D3 and 1,25(OH)2D3 serum concentration and breast tissue expression of 1alpha-hydroxylase, 24-hydroxylase and vitamin D receptor in women with and without breast cancer. J Steroid Biochem Mol Biol. 2006, 100: 184-192.
Friedrich M, Rafi L, Mitschele T, Tilgen W, Schmidt W, Reichrath J: Analysis of the vitamin D system in cervical carcinomas, breast cancer and ovarian cancer. Recent Results Cancer Res. 2003, 164: 239-246.
Segersten U, Holm PK, Bjorklund P, Hessman O, Nordgren H, Binderup L, Akerstrom G, Hellman P, Westin G: 25-Hydroxyvitamin D3 1alphahydroxylase expression in breast cancer and use of non-1alphahydroxylated vitamin D analogue. Breast Cancer Res. 2005, 7: R980-986.
Townsend K, Banwell CM, Guy M, Colston KW, Mansi JL, Stewart PM, Campbell MJ, Hewison M: Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin Cancer Res. 2005, 11: 3579-3586.
Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchio C, Reis-Filho JS: Breast cancer precursors revisited: molecular features and progression pathways. Histopathology. 2010, 57: 171-192.
Jensen SS, Madsen MW, Lukas J, Binderup L, Bartek J: Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery. Mol Endocrinol. 2001, 15: 1370-1380.
Verlinden L, Verstuyf A, Convents R, Marcelis S, Van Camp M, Bouillon R: Action of 1,25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells. Mol Cell Endocrinol. 1998, 142: 57-65.
Wu G, Fan RS, Li W, Ko TC, Brattain MG: Modulation of cell cycle control by vitamin D3 and its analogue, EB1089, in human breast cancer cells. Oncogene. 1997, 15: 1555-1563.
Saunders DE, Christensen C, Wappler NL, Schultz JF, Lawrence WD, Malviya VK, Malone JM, Deppe G: Inhibition of c-myc in breast and ovarian carcinoma cells by 1,25-dihydroxyvitamin D3, retinoic acid and dexamethasone. Anticancer Drugs. 1993, 4: 201-208.
Dhawan P, Wieder R, Christakos S: CCAAT enhancer-binding protein alpha is a molecular target of 1,25-dihydroxyvitamin D3 in MCF-7 breast cancer cells. J Biol Chem. 2009, 284: 3086-3095.
Beildeck ME, Islam M, Shah S, Welsh J, Byers SW: Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines. PLoS One. 2009, 4: e7872-
Campbell MJ, Gombart AF, Kwok SH, Park S, Koeffler HP: The anti-proliferative effects of 1alpha,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression. Oncogene. 2000, 19: 5091-5097.
Krishnan AV, Swami S, Peng L, Wang J, Moreno J, Feldman D: Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy. Endocrinology. 2010, 151: 32-42.
Simboli-Campbell M, Narvaez CJ, Tenniswood M, Welsh J: 1,25-Dihydroxyvitamin D3 induces morphological and biochemical markers of apoptosis in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 1996, 58: 367-376.
Weitsman GE, Ravid A, Liberman UA, Koren R: Vitamin D enhances caspase-dependent and -independent TNFalpha-induced breast cancer cell death: The role of reactive oxygen species and mitochondria. Int J Cancer. 2003, 106: 178-186.
Narvaez CJ, Welsh J: Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells. J Biol Chem. 2001, 276: 9101-9107.
Hoyer-Hansen M, Nordbrandt SP, Jaattela M: Autophagy as a basis for the health-promoting effects of vitamin D. Trends Mol Med. 2010, 16: 295-302.
Koren R, Hadari-Naor I, Zuck E, Rotem C, Liberman UA, Ravid A: Vitamin D is a prooxidant in breast cancer cells. Cancer Res. 2001, 61: 1439-1444.
Welsh J: Induction of apoptosis in breast cancer cells in response to vitamin D and antiestrogens. Biochem Cell Biol. 1994, 72: 537-545.
Ravid A, Rocker D, Machlenkin A, Rotem C, Hochman A, Kessler-Icekson G, Liberman UA, Koren R: 1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. Cancer Res. 1999, 59: 862-867.
Wang Q, Yang W, Uytingco MS, Christakos S, Wieder R: 1,25-Dihydroxyvitamin D3 and all-trans-retinoic acid sensitize breast cancer cells to chemotherapy-induced cell death. Cancer Res. 2000, 60: 2040-2048.
Cho YL, Christensen C, Saunders DE, Lawrence WD, Deppe G, Malviya VK, Malone JM: Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells. Cancer Res. 1991, 51: 2848-2853.
Stambolsky P, Tabach Y, Fontemaggi G, Weisz L, Maor-Aloni R, Siegfried Z, Shiff I, Kogan I, Shay M, Kalo E, Blandino G, Simon I, Oren M, Rotter V: Modulation of the vitamin D3 response by cancer-associated mutant p53. Cancer Cell. 2010, 17: 273-285.
Hansen CM, Frandsen TL, Brunner N, Binderup L: 1 alpha,25-Dihydroxyvitamin D3 inhibits the invasive potential of human breast cancer cells in vitro. Clin Exp Metastasis. 1994, 12: 195-202.
Koli K, Keski-Oja J: 1alpha,25-dihydroxyvitamin D3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells. Cell Growth Differ. 2000, 11: 221-229.
Sundaram S, Beckman MJ, Bajwa A, Wei J, Smith KM, Posner GH, Gewirtz DA: QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells. Mol Cancer Ther. 2006, 5: 2806-2814.
El Abdaimi K, Dion N, Papavasiliou V, Cardinal PE, Binderup L, Goltzman D, Ste-Marie LG, Kremer R: The vitamin D analogue EB 1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells. Cancer Res. 2000, 60: 4412-4418.
Pendas-Franco N, Gonzalez-Sancho JM, Suarez Y, Aguilera O, Steinmeyer A, Gamallo C, Berciano MT, Lafarga M, Munoz A: Vitamin D regulates the phenotype of human breast cancer cells. Differentiation. 2007, 75: 193-207.
Paredes J, Stove C, Stove V, Milanezi F, Van Marck V, Derycke L, Mareel M, Bracke M, Schmitt F: P-cadherin is up-regulated by the antiestrogen ICI 182,780 and promotes invasion of human breast cancer cells. Cancer Res. 2004, 64: 8309-8317.
Lopes N, Carvalho J, Duraes C, Sousa B, Gomes M, Costa JL, Oliveira C, Paredes J, Schmitt F: 1Alpha,25-dihydroxyvitamin D3 Induces de novo E-cadherin Expression in Triple-negative Breast Cancer Cells by CDH1-promoter Demethylation. Anticancer Res. 2012, 32: 249-257.
Oikawa T, Hirotani K, Ogasawara H, Katayama T, Nakamura O, Iwaguchi T, Hiragun A: Inhibition of angiogenesis by vitamin D3 analogues. Eur J Pharmacol. 1990, 178: 247-250.
Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE: 1 alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res. 2000, 87: 214-220.
Gonzalez-Sancho JM, Alvarez-Dolado M, Munoz A: 1,25-Dihydroxyvitamin D3 inhibits tenascin-C expression in mammary epithelial cells. FEBS Lett. 1998, 426: 225-228.
Matsumoto H, Iino Y, Koibuchi Y, Andoh T, Horii Y, Takei H, Horiguchi J, Maemura M, Yokoe T, Morishita Y: Antitumor effect of 22-oxacalcitriol on estrogen receptor-negative MDA-MB-231 tumors in athymic mice. Oncol Rep. 1999, 6: 349-352.
Smeets SJ, Harjes U, van Wieringen WN, Sie D, Brakenhoff RH, Meijer GA, Ylstra B: To DNA or not to DNA? That is the question, when it comes to molecular subtyping for the clinic!. Clin Cancer Res. 2011, 17: 4959-4964.
The authors declare that they have no competing interests.
About this article
Cite this article
Lopes, N., Paredes, J., Costa, J.L. et al. Vitamin D and the mammary gland: a review on its role in normal development and breast cancer. Breast Cancer Res 14, 211 (2012). https://doi.org/10.1186/bcr3178
- Breast Cancer
- Mammary Gland
- Breast Cancer Risk
- Normal Mammary Gland
- Columnar Cell Lesion