Vitamin D deficiency : a worldwide problem with health consequences

https://www.arcarmichael.com/VitaminD/Cancers/garland_vit_d_cancer_prev.pdf

Vitamin D for Cancer Prevention: Global Perspective

Vitamin D has pleiotropic effects that go beyond its traditional role in calcium homeostasis. Hundreds of genes with vitamin D receptor response elements directly or indirectly influence cell cycling and proliferation, differentiation, and apoptosis. Vitamin D compounds also have effects on cell function that are nongenomic. The noncalcemic actions of vitamin D influence normal and pathological cell growth, carcinogenesis, immune function, and cardiovascular physiology. This review examines many of the various mechanisms by which vitamin D alters cellular growth and differentiation and explores cell-specific factors that influence responsiveness to vitamin D.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1753-4887.2008.00094.x

Vitamin D's role in cell proliferation and differentiation

It is now well established that, in addition to its central role in the maintenance of extracellular calcium levels and bone mineralization, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, also acts as a modulator of cell growth and differentiation in a number of cell types, including breast cancer cells. The anti-proliferative effects of 1,25(OH)(2)D(3) have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21(WAF-1/CIP1) and p27(kip1), cyclins and retinoblastoma protein as well as induction of apoptosis. Such studies have led to interest in the potential use of 1,25(OH)(2)D(3) in the treatment or prevention of certain cancers. Since this approach is limited by the tendency of 1,25(OH)(2)D(3) to cause hypercalcaemia, synthetic vitamin D analogues have been developed which display separation of the growth regulating effects from calcium mobilizing actions. This review examines mechanisms by which 1,25(OH)(2)D(3) and its active analogues exert both anti-proliferative and pro-apoptotic effects and describes some of the synthetic analogues that have been shown to be of particular interest in relation to breast cancer.

/pdf/mechanisms-implicated-in-the-growth-regulatory-effects-of-3gcznq202m.pdf

Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer.

Vitamin D and breast cancer: insights from animal models

Our studies have identified 1,25(OH)2D3 as a coordinate regulator of proliferation and apoptosis in breast cancer cells. In MCF-7 cells, 1,25(OH)2D3 down regulates the estrogen receptor (ER), suggesting that the effects of 1,25(OH)2D3 may be linked to disruption of estrogen regulated survival signals. Although studies have demonstrated that 1,25(OH)2D3 inhibits growth of ER negative breast cancer cells, previous data were generated by comparison of cell lines derived from heterogeneous human tumors and harboring diverse genetic alterations. To provide more conclusive evidence for independent growth regulatory pathways mediated by antiestrogens and 1,25(OH)2D3, we examined vitamin D3 sensitivity in MCF-7 cells selected for resistance to ICI 182, 780 (Zeneca, Macclesfield, UK). The clones we selected for resistance to ICI 182,780 retain functional VDR and undergo 1,25(OH)2D3 mediated growth arrest and apoptosis, in vitro and in vivo, despite loss of estrogen dependence. Cell cycle data indicate that treatment of parental or anti-estrogen resistant MCF-7 clones with 1,25(OH)2D3, in the presence or absence of ICI 182,780, increases the percentage of cells in G0/G1 while reducing the number of cells in S phase. In addition, 1,25(OH)2D3 induces characteristic features of apoptosis, including DNA fragmentation, in both parental and anti-estrogen resistant MCF-7 cells. Furthermore, we report that cells selected for vitamin D3 resistance retain sensitivity to ICI 182,780 mediated growth arrest and apoptosis. This work emphasizes that vitamin D3 compounds and anti-estrogens trigger growth arrest and apoptosis in breast cancer cells by distinct mechanisms, and that breast cancer cell sensitivity to 1,25(OH)2D3 is not diminished during the progression to estrogen independence. (Mol Cell Biochem 188: 13-20, 1998)

Dissociation of vitamin D3 and anti-estrogen mediated growth regulation in MCF-7 breast cancer cells

The death of cells can be classified as either necrosis, usually the result of tissue damage or insult, or apoptosis, an active process of cellular self-destruction. Apoptosis can be distinguished by its characteristic morphological features such as cell shrinkage, nuclear condensation, and irreversible DNA fragmentation (Tenniswood et al., 1992). In most cell types, apoptosis requires gene transcription and activation of specific proteases which mediate destruction of the cell without release of intracellular contents or initiation of an immune response (Vaux and Strasser, 1996; Zhivotovsky et al., 1997). In addition to genes linked to activation of apoptosis, genes associated with repression of apoptosis, such as bcl-2, have been identified (Craig, 1995; Yang and Korsmeyer, 1996). Thus, the regulation of apoptosis within a cell reflects a balance between antiapoptotic and proapoptotic gene products. Extracellular influences on this balance include physiological triggers of apoptosis, cell-type-specific “survival factors,” and the components of the extracellular matrix (Tenniswood et al., 1992; Goberdhan et al., 1996; Merio et al., 1997). The recognition that mutations in critical components or regulators of the apoptotic pathway, such as p53 and bcl-2, may be linked to cancer development or therapeutic responsiveness has emphasized the importance of apoptosis in the context of tumor biology (Barry et al., 1990; Lowe et al., 1993; Yang and Korsmeyer, 1996).

Elizabeth Nolan

Papers

Dissociation of vitamin D3 and anti-estrogen mediated growth regulation in MCF-7 breast cancer cells

The role of vitamin D3 and antiestrogens in modulating apoptosis of breast cancer cells and tumors.