Page 300 - Vitamin D and Cancer

12 The Vitamin D Signaling Pathway in Mammary Gland and Breast Cancer 287

and calcium, high in saturated fat) exhibited hyperproliferation in the mammary
gland and developed significantly more mammary tumors when treated with
7,12-dimethylbenzanthracence (DMBA) compared to rats fed adequate calcium
and vitamin D (reviewed by [56]). In mouse mammary gland organ culture,
1,25D and the synthetic analog 1a(OH)D reduced the incidence of preneoplas-
5
tic lesions in response to DMBA during both the initiation and the promotion
stages, demonstrating that vitamin D compounds exert direct antineoplastic
effects on mammary gland at multiple steps [57]. Prevention of N-methyl-N-
nitrosourea-induced mammary tumors with vitamin D analogs, including
Ro24–5531 (1,25-dihydroxy-16-ene-23-yne-26–27-hexafluorocholecalciferol)
and 1a(OH)D provided further support that the vitamin D pathway may protect
5
against breast cancer in vivo [58, 59].

12.5 Mammary Gland Development and Carcinogenesis
in VDR Null Mice

Mice lacking the VDR demonstrate excess proliferation and branching as well
as impaired apoptosis during the reproductive cycle compared to their normal
counterparts [51, 52]. Organ culture experiments indicated that 1,25D blocked
the growth stimulatory effects of estrogen and progesterone in glands from
wild-type mice but was without effect in glands from VDR null mice, indicat-
ing that the VDR acts in a ligand dependent manner to mediate negative
growth signaling directly in mammary tissue. Comparison of gene expression
in normal and VDR null mice has identified cyclin D1, p21, clusterin,
b-catenin and TGFb1 as potential VDR target genes in the mammary gland
in vivo (Zinser, Matthews and Welsh, unpublished data). Demonstration that
VDR ablation alters growth regulatory pathways in mammary gland raised the
possibility that VDR null mice might display enhanced risk for cancer devel-
opment in this tissue. Indeed, the incidence of mammary hyperplasias and
development of ER negative tumors in response to the carcinogen DMBA was
higher in VDR null mice than their WT counterparts [60]. Furthermore, on the
MMTV-neu transgenic background (a model of her2 positive human breast
cancer), VDR heterozygote mice demonstrated higher incidence of mammary
tumors than did WT mice [61]. Notably, differences in cancer susceptibility
were not limited to the mammary gland, as VDR null mice displayed increased
sensitivity to tumors in the lymph nodes and skin in response to DMBA com-
pared to WT mice [60, 62]. These in vivo studies have provided the most direct
evidence that VDR signaling can protect against cancer development.
Collectively, these and other animal studies have confirmed that the effects of
vitamin D signalling observed in vivo translate to effects on cell proliferation,
differentiation and apoptosis in vivo that are of sufficient magnitude to impact
on the carcinogenic process.