Page 296 - Vitamin D and Cancer

12 The Vitamin D Signaling Pathway in Mammary Gland and Breast Cancer 283

up to 4,000 IU/day for individuals with limited sun exposure) is needed to maintain
serum 25D at 100 nM, but further research is needed on vitamin D supplementation
in relation to chronic disease. One small, double blinded intervention study of
healthy post-menopausal women indicated that daily supplementation with
1,100 IU vitamin D reduced cancer risk at all sites [19]. Collectively, these
3
observations provide initial evidence that vitamin D may reduce breast cancer
incidence, and emphasize the need for re-evaluation of public health recommenda-
tions regarding sun exposure, vitamin D intake, food fortification and supplement
use in relation to vitamin D status and breast cancer.

12.3 Mechanistic Links Between Vitamin D and Breast Cancer

12.3.1 General Effects of VDR Agonists in Breast Cancer Cells

In response to the initial identification of VDR in cancer cells, numerous studies
examined the effects of 1,25D on breast cancer cells. Furthermore, a large number of
structural analogs of vitamin D, developed by pharmaceutical companies and aca-
demic researchers, have been used to probe the mechanisms of vitamin D mediated
growth inhibition. In general, the effects of VDR agonists on breast cancer cells are
similar to those reported in other cancer cell types: modulation of key cell cycle regu-
lators to arrest the cycle at either G0/G1 or G2/M (depending on cell type), induction
of differentiation markers, and/or activation of cell death (via apoptosis or autophagy).
Mechanisms have recently been reviewed in detail [20, 21], and thus are briefly
discussed here. Notably, studies with cells derived from VDR null mice has definitely
established that the VDR is required for the antiproliferative and proapoptotic effects
of 1,25D in transformed mammary cells in vitro [22, 23].

12.3.2 Cellular and Molecular Targets of VDR
in Breast Cancer Cells

Screening for molecular changes induced by 1,25D or vitamin D analogs in various
breast cancer cells has identified scores of VDR regulated genes and proteins in
diverse pathways, indicating a broad range of downstream targets [24–26]. The
induction of cell cycle arrest in both estrogen receptor positive and negative breast
cancer cells by 1,25D results from alterations in key cell cycle regulators including
cyclin D1, the cyclin dependent kinase inhibitors p21 and/or p27 and the retinoblas-
toma protein. 1,25D also blocks mitogenic signaling, including that of estrogen,
EGF, IGF-1 and KGF and up-regulates negative growth factors such as TGFb
[27–29]. In many breast cancer cell lines, 1,25D mediated growth arrest is associated
with the induction of differentiation markers such as casein, lipid droplets, and adhe-