The answer to the question to whether Vitamin D is responsible for Breast Cancer?
Sayan Basak
Dr. Priyanjali Datta
Aaroogya India (http://www.aaroogya.org/)
Introduction
The main role of vitamin D is as a modulator of calcium homeostasis and osteosynthesis, and it also contributes to the correct functioning of the immune, muscular and nervous systems. Vitamin D is difficult to obtain through the diet because very few foods naturally contain the vitamin, exceptions being the liver of fatty fish and fortified milk. Skin is the primary natural source of vitamin D. Although there is an optimum level of the Vitamin D content in every human being which primarily depends upon the metabolic rate, the calorific expenditure and the cognitive process; researches say that too much synthesis of Vitamin D is harmful to our immune system. Through a cascade chain of reactions and biochemical pathways, a particular strand of Vitamin D known as the 25OHD is finally converted to calcitroic acid which in turn gets excreted.
Vitamin D and its role in the prevention of metastasis
The discovery that epithelial breast cells possess thesame enzyme system as the kidney renders the effect ofvitamin D on breast cancer biologically plausible. Experimental, preclinical and ecological studies have shown that this particular strand of Vitamin D inhibits cell proliferation and angiogenesis in normaland malignant breast cells. Similar associations have been reported in observational studies. Researchers claim that this strand of the vitamin D is inversely proportional to the process of oncogenisis. In human cell lines derived from normal breast tissueand in breast cancer cells Vitamin D interfere with cell cycle arrest, differentiation andapoptosis, depending on autophagy, the particular type ofcell, cellular microenvironment and the activity of other signalling pathways. In addition, human mammarycells cultured from normal breast tissue express VDR,CYP27B1 and the megalin-cubilin complex. This complex is present in the plasma membrane of epithelial cells of thekidney proximal tubule, as a major glycoprotein uptake complex with a nutritional, catabolic and resorption function, promoting fixation of the complexes formed between25OHD and its binding protein DBP (vitamin D binding protein) which inhibits the growth of the malignant tumour.

The Bio-chemistry behind the discovery
Although limited in scope, these data suggest that avitamin D deficiency sufficient to reduce the availability ofsubstrate for CYP27B1 and limit production of 1,25OH2D could result in deregulation of tumour suppressor pathwaystriggered by VDR.When incubated with physiological concentrations of 25-hydroxyvitamin D (25OHD), human mammary cells synthesise1,25OH2D in sufficient quantity to mediate growth inhibition.However, the concentrations of 1,25OH2D necessary tomediate these effects against cancer (100 nmol/L) are wellabove the physiological range and are associated withundesirable side effects in vivo. Based on these considerations,it is unlikely that 1,25OH2D acts at systemic level toregulate the growth of mammary cells in vivo. However,identification of CYP27B1 in skin, colon, prostate and breast suggests that when generated locally, 1,25OH2D might act inan autocrine or paracrine manner to protect cells againstcancerous transformation.VDR expression is dynamically regulated in the mammarygland throughout the reproductive cycle and is necessary forproperglandular development during puberty, pregnancy and breast involution. In mammary gland cell cultures, VDRagonists, including 1,25OH2D, inhibit ductal proliferationinduced by oestrogens and VDR-dependent branching andprotect against chemically induced pre-neoplastic lesions.Compared with glands from normal mice, the glands of micewithout VDR expression exhibit accelerated developmentduring puberty and pregnancy and reduced apoptosis duringpost-lactation involution, indicating that VDR acts to regulatethe proliferation, differentiation and apoptosis ofbreast tissue in a physiological context.In contrast with CYP27B1, CYP24A1 expression is notusually detectable in non-cancer cells in the absence ofVDR activity, but is highly induced by supplemental treatmentwith 1,25OH2D.The relative activity of CYP27B1 and CYP24A1 willdetermine whether VDR is activated or vitamin D is catabolisedfrom 25OHD. In human mammary cells and culturecells of murine organs, 25OHD induces transcription of VDR,suggesting that at baseline, CYP27B1 activity predominatesover CYP24 activity, resulting in the net conversion of25OHD to 1,25OH2D.
The data above support the notion that circulating25OHD attached to DBP is internalised by normal mammarycells and becomes 1,25OH2D, which interacts with VDR inthe same place or in adjacent cells to maintain differentiationand quiescence in the breast epithelium. This hypothesispredicts that the interruption of any of themultiple steps in the transport, metabolism or function of25OHD could contribute to the development or progression of breast cancer.

Conclusion
In short, the components of the endocrine signallingsystem of vitamin D that are definitively expressed innormal human mammary gland include VDR, CYP27B1, CYP24A1 and megalin. The expression of most of thesegenes is altered in conjunction with the development ofbreast cancer, usually through epigenetic mechanisms. The data connecting the development of breast cancer and Vitamin D is still in its developmental stage since it researches are still going on the field to mark optimum amount of Vitamin D required to escalate the beneficial effects on the mammary epithelial cells.
Furthermore, some research suggests that women with lowlevels of vitamin D present a higher risk of breast cancer.Breast cancer is a heterogeneous disease and it is possible thatvitamin D only affects certain subtypes of breast cancer.Although there is still much to learn about the mechanismsby which breast cells process and respond to 25OHD,the available data are consistent with a protective role ofthis vitamin D metabolite with respect to breast cancer.
References
[1] Garland C, Garland F, Gorham E, Lipkin M, Newmark H, Mohr S, et al. The role of vitamin D in cancer prevention. Am J Public Health 2006;96:252e61.
[2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893e917.
[3] Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981;66:1191e308.
[4] Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 2014;14:342e57.
[5] Brock KE, Graubard BI, Fraser DR, Weinstein SJ, Stolzenberg- Solomon RZ, Lim U, et al. Predictors of vitamin D biochemical status in a large sample of middle-aged male smokers in
Finland. Eur J Clin Nutr2010;64:280e8.
[6] Chan J, Jaceldo-Siegl K, Fraser GE. Determinants of serum 25 hydroxyvitamin D levels in a nationwide cohort of blacks and non-Hispanic whites. Cancer Causes Control 2010;21:501e11.
[7] Jorde R, Sneve M, Emaus N, Figenschau Y, Grimnes G. Crosssectional and longitudinal relation between serum 25- hydroxyvitamin D and body mass index: the Tromso study. Eur J Nutr2010;49:401e7.