Page 293 - Vitamin D and Cancer

280 G.M. Zinser et al.

Abbreviations

1,25D 1,25 Dihydroxyvitamin D
DBP D binding protein
DMBA Dimethylbenzanthracene
EGF Epidermal growth factor
HME Human mammary epithelial
25D 25 Hydroxyvitamin D
IGF-1 Insulin like growth factor 1
KGF Keratinocyte growth factor
SV40 Simian virus 40
TGFb Transforming growth factor beta
UV Ultraviolet
VDR Vitamin D receptor
WT Wild type

12.1 Introduction to Vitamin D and Breast Cancer

Although originally identified based on its ability to prevent the bone disease
rickets, it is now recognized that 1a,25 dihydroxyvitamin D (1,25D), the bio-
3
logically active form of vitamin D , is a global regulator of gene expression and
3
signal transduction in virtually every tissue. In breast cells, the vitamin D recep-
tor (VDR) and its ligand 1,25D contribute to maintenance of the quiescent, dif-
ferentiated phenotype, providing defense against cancer development. The
presence of functional VDR in the majority of human breast tumors (initially
discovered over 25 years ago) suggested that this receptor might represent a
target for breast cancer therapy. Since that time, multiple studies have confirmed
the antiproliferative effects of vitamin D on breast cancer cells in vitro and
rodent tumors in vivo. Dozens of synthetic vitamin D structural analogs have
been tested for efficacy and side effects in animal models of cancer, individually
and in combination with standard therapies such as anti-estrogens, chemothera-
peutic drugs and radiation. While these studies have generally been supportive
of targeting the vitamin D pathway in breast cancer therapy, issues of dosing,
toxicity and efficacy (particularly against various tumor sub-types) remain to be
resolved.
More recently, studies have focused on characterization of the expression and
function of the vitamin D pathway in normal mammary tissue and the possible role
of the vitamin D pathway in breast cancer prevention. In particular, data from the
VDR knockout mouse model have indicated that complete abrogation of vitamin D
signaling alters glandular morphology and susceptibility to cancer development. In
this review, we will summarize the currently available data generated from both
in vitro and in vivo studies, with an emphasis on the cellular and molecular mecha-
nisms by which vitamin D may contribute to breast cancer prevention.