Page 53 - Vitamin D and Cancer

40 J. Thorne and M.J. Campbell

poly(A) sequence within the 3¢UTR, which in turn determines transcript stability.
Interestingly, combined polymorphisms and serum 25OH-D levels have been
shown to compound breast cancer risk and disease severity further [182].
Earlier studies suggested that polymorphisms in the VDR gene might also be
associated with risk factor of prostate cancer. Ntais and coworkers performed a
meta-analysis of 14 published studies with four common gene polymorphisms
(Taq1, poly A repeat, Bsm1, and Fok1) in individuals of European, Asian, and
African descent. They concluded that these polymorphisms are unlikely to be major
determinants of susceptibility to prostate cancer on a wide population basis [183].
Equally, studies in colon cancer have yet to reveal conclusive relationships and may
be dependent upon ethnicity of the population studied.

2.4.4 Epigenetic Resistance

In cancer cells, the lack of an antiproliferative response is reflected by a suppres-
sion of the transcriptional responsiveness of anti-proliferative target genes such
as CDKN1A CDKNIB, GADD45A and IGFBPs, BRCA1 [120, 135, 184, 185].
Paradoxically, VDR transactivation of other targets is sustained or even
enhanced, as measured by induction of the highly 1a25(OH) D -inducible
2 3
CYP24 gene [186, 187]. Together these data suggest that the lack of functional
VDR alone cannot explain resistance and instead the VDR transcriptome is
skewed in cancer cells to disfavor anti-proliferative target genes. It has been
proposed that this apparent 1a,25(OH) D -insensitivity is the result of epige-
2 3
netic events that selectively suppress the ability of the VDR to transactivate
target genes [188].
The epigenetic basis for such transcriptional discrepancies has been investigated
intensively in prostate cancer. VDR-resistant prostate cancer cells are associated
with elevated levels of NCOR2/SMRT [135, 184]; these data indicate that the ratio
of VDR to corepressor may be critical to determine 1a,25(OH) D responsiveness
2 3
in cancer cells. An siRNA approach toward NCoR2/SMRT demonstrated a role for
this corepressor to regulate this response GADD45a in response to 1a,25(OH) D .
2 3
By contrast, knockdown of NCOR1 does not restore anti-proliferative responsive-
ness toward 1a,25(OH) D but does reactivate transcriptional networks governed
2 3
by PPARs [189]. These data support a central role for elevated NCOR2/SMRT
levels to suppress the induction of key target genes, resulting in loss of sensitivity
to the anti-proliferative action of 1a,25(OH) D ; other workers have reinforced
2 3
these concepts [190, 191].
Parallel studies have demonstrated a similar spectrum of reduced 1a,25(OH) D -
2 3
responsiveness between nonmalignant breast epithelial cells and breast cancer cell
lines. Again, this was not determined solely by a linear relationship between the
levels of 1a,25(OH) D and VDR expression. Rather, elevated corepressor mRNA
2 3
levels, notably of NCoR1, in ERa negative breast cancer cell lines and primary
cultures, were associated with 1a,25(OH) D insensitivity [192]. Elevated NCOR1
2 3