Page 52 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 39

signaling. For example, Munoz and coworkers have dissected the interrelationships
between the VDR, E-cadherin, and the Wnt signaling pathway in colon cancer cell
lines and primary tumors. In these studies, the induction of CDH1 (encodes
E-Cadherin) was seen in subpopulations of SW480 colon cancer cells, which
express the VDR and respond to 1a,25(OH) D . The VDR thereby limits the tran-
2 3
scriptional effects of b-catenin by physically and directly binding it in the nucleus,
and by upregulating E-cadherin to sequestrate b-catenin in the cytoplasm. In malig-
nancy, these actions are corrupted through downregulation of VDR mRNA, which
appears to be a direct consequence of binding by the transcriptional repressor
SNAIL; a key regulator of the epithelial-mesenchyme transition, which is overex-
pressed in colon cancer [168–170]. Equally underscoring the central importance of
b-catenin, it has recently been shown to be posttranslationally modified to act as
VDR coactivator and supports a model of checks and balances between these two
signaling processes [168, 171].

2.4.3 Genetic Resistance

In cancer, and outside of the very limited pool of mutations reported in the VDR in
type II rickets, the receptor, generally, is neither mutated nor does it appear to be
the subject of cytogenetic abnormalities [172]. By contrast, polymorphic variations
of the VDR have been widely reported. Thus polymorphisms in the 3¢ and 5¢ regions
of the gene have been described and variously associated with risk of breast, pros-
tate, and colon cancer, although the functional consequences remain to be estab-
lished clearly. For example, a start codon polymorphism in exon II at the 5¢ end of
the gene, determined using the fok-I restriction enzyme, results in a truncated pro-
tein. At the 3¢ end of the gene, three polymorphisms have been identified that do
not lead to any change in either the transcribed mRNA or the translated protein. The
first two sequences generate BsmI and ApaI restriction sites and are intronic, lying
between exons 8 and 9. The third polymorphism, which generates a TaqI restriction
site, lies in exon 9 and leads to a silent codon change (from ATT to ATC) which
both inserts an isoleucine residue at position 352. These three polymorphisms are
linked to a further gene variation, a variable length adenosine sequence within the
3¢ untranslated region (3¢UTR). The poly(A) sequence varies in length and can be
segregated into two groups; long sequences of 18–24 adenosines or short ones
[173–176]. The length of the poly(A) tail can determine mRNA stability [177–179]
so the polymorphisms resulting in long poly(A) tails may increase the local levels
of the VDR protein.
Multiple studies have addressed the association between VDR genotype and
cancer risk and progression. In breast cancer, the ApaI polymorphism shows a sig-
nificant association with breast cancer risk, as indeed have BsmI and the “L”
poly(A) variant. Similarly, the ApaI polymorphism is associated with metastases to
bone [180, 181]. The functional consequences of the BsmI, ApaI, and TaqI poly-
morphisms are unclear, but because of genetic linkage may act as a marker for the