Page 298 - Vitamin D and Cancer

12 The Vitamin D Signaling Pathway in Mammary Gland and Breast Cancer 285

tumors in animal models [44, 45]. The effects of vitamin D analogs were comparable
to standard anti-estrogen therapies such as tamoxifen, and additive effects were
observed in combination studies (with tamoxifen, ionizing radiation, and chemothera-
peutic drugs). Vitamin D analog therapy was effective in both estrogen receptor posi-
tive and estrogen receptor negative xenografts [45–47]. Under the conditions utilized
in these in vivo studies, the vitamin D analogs did not cause weight loss or hypercal-
cemia, but the therapeutic window for most of these compounds is narrow. Of particu-
lar interest, studies on xenografts derived from WT and VDR null cells indicated that
expression of functional VDR in tumor epithelial cells (rather than in accessory cells
such as fibroblasts, immune cells or endothelial cells) is necessary for the antitumor
effects of the vitamin D analog EB1089 and UV generated vitamin D in vivo [48].

12.4 Evidence for Breast Cancer Prevention by Vitamin D

12.4.1 VDR Expression in Normal Mammary Cells

The link between vitamin D and breast cancer prevention is based on the concept
that the 1,25D-VDR complex promotes or maintains the differentiated phenotype in
normal mammary cells. Consistent with this concept, the VDR is expressed in nor-
mal mammary epithelial tissue in vivo and in nontransformed human mammary
epithelial (HME) cells in vitro [49–51]. In mouse mammary gland, VDR is localized
predominantly in differentiated epithelial cells, and its expression increases 100-fold
during the course of pregnancy and lactation [51, 52]. The mammary epithelial cells
are organized in ducts which are contained within an extensive adipose rich stromal
compartment (the mammary fat pad) which includes fibroblasts, adipocytes,
endothelial cells, immune cells, and extracellular matrix proteins. VDR is also
expressed in the stromal fibroblasts, the mammary adipocytes, and the infiltrating
immune cells, indicating potential cross-talk between compartments. A potential
role of vitamin D signaling in the mammary adipocytes is supported by the demon-
stration that lipophilic vitamin D steroids are stored in fat [53] and by the presence
of both VDR and Cyp27B1 expression and activity in human adipocytes (Zinser,
unpublished). A working model for the cross-talk between cells in the epithelial,
stromal and adipose compartments of the breast is provided in Fig. 12.2.

12.4.2 Vitamin D Metabolites Mediate Growth Inhibition
in Normal Mammary Cells

The function of the vitamin D pathway in nontransformed HME cells has recently
been evaluated. The effects of 1,25D on HME cells include growth arrest and
induction of differentiation markers such as E-cadherin, but apoptosis has not been
observed [50]. Notably, mammary cells express Cyp27B1, can generate 1,25D