Abstract
Vitamin D3 (vitD3) and its active metabolite, calcitriol (1,25-(OH)2D3), affect multiple tissue types by interacting with the vitamin D receptor (VDR). Although vitD3 deficiency has been correlated with increased incidence of breast cancer and less favorable outcomes, randomized clinical trials have yet to provide conclusive evidence on the efficacy of vitD3 in preventing or treating breast cancer. Additionally, experimental studies are needed to assess the biological plausibility of these outcomes. The mammary gland of VDR KO mice shows a florid phenotype revealing alterations of developmental processes that are largely regulated by mammotropic hormones. However, most research conducted on vitD3’s effects used 2D cell cultures and supra-physiological doses of vitD3, conditions that spare the microenvironment in which morphogenesis takes place. We investigated the role of vitD3 in mammary epithelial morphogenesis using two 3D culture models. VitD3 interfered with estrogen’s actions on T47D human breast cancer cells in 3D differently at different doses, and recapitulated what is observed in vivo. Also, vitD3 can act autonomously and affected the organization of estrogen-insensitive MCF10A cells in 3D collagen matrix by influencing collagen fiber organization. Thus, vitD3 modulates mammary tissue organization independent of its effects on cell proliferation.
Highlights
Breast cancer remains a major cause of mortality among women worldwide
Despite evidence linking Vitamin D3 (vitD3) deficiency to increased risk of breast cancer and worse clinical outcomes in patients, randomized clinical trials have yet to confirm the efficacy of vitD3 as a preventive or therapeutic option in this disease[8]
While vitamin D receptor (VDR) KO mice do not develop tumors spontaneously, mammary glands from these mice exhibit a striking phenotype of excessive and precocious development at key stages[15,16]. This suggests that vitD3 plays an important role in the development of the normal mammary gland
Summary
Breast cancer remains a major cause of mortality among women worldwide. Epidemiological studies have shown that key stages during breast development are susceptible to the effects of carcinogens. Mammary glands of VDR KO mice exhibited a florid developmental phenotype, as exemplified by increased number of terminal end buds, increased ductal extension and lateral branching at puberty[15], precocious alveologenesis during pregnancy, and delayed post-lactational involution[16] These developmental processes are largely influenced by the so-called mammotropic hormones, i.e., Estrogen (E), Progesterone (Prg) and Prolactin (Prl). Most studies have used a calcitriol dose of 100 nM, a dose chosen based on the deficiency cut-off level for vitD3 in human populations that is determined by measuring the serum levels of calcidiol, the precursor to calcitriol[18] Utilizing such a dose assumes a hundred percent conversion rate of calcidiol to calcitriol locally at specific tissues, while not taking into account that calcitriol may elicit a non-monotonic dose response comparable to that observed with other steroid hormones
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