Page 47 - Vitamin D and Cancer

34 J. Thorne and M.J. Campbell

required [107]. Notably, the corepressor, Hairless plays a clear role in hair
formation with either knockout or mutation resulting in alopecia strikingly similar
to that observed in the Vdr null mice [108, 109].
Wnt signaling is one of the major processes regulating postmorphogenic hair
follicle development. Interestingly, the development of dermal cysts and increase
in sebaceous glands observed in the Vdr and Hairless -/- mice are also similar to
mice expressing a keratinocyte-specific disruption to b-catenin [110, 111].
These findings have raised the possibility that one function of the Vdr may be to
co-regulate aspects of Wnt signaling, a concept that is supported further by the
physical association of VDR in a complex with b-catenin and other Wnt compo-
nents [112].
Another unexpected finding of the Vdr -/- animals was the uterine hypoplasia and
impaired ovarian function in the females that leads to dramatically reduced fertility.
Similarly to the hair phenotype, this was not restored by the rescue diet of high
calcium [94]. Estradiol supplementation, however, of the female mice restored
uterine function and fertility and suggests the fault lies with an inability to generate
estrogen. The mammary gland has also been studied extensively, in a comprehen-
sive series of experiments by Welsh and coworkers [113, 114] and represents
an intriguing tissue where endocrine (calcemic8) and autocrine (antimitotic,
pro-differentiative, pro-apoptotic) effects of the VDR appear to converge.
These phenotypes underscore the integrated nature of VDR signaling. That is,
the biology of hair regeneration and mammary gland function reflects the choreo-
graphed actions of VDR, with other NRs, alongside other regulatory processes
including Wnt signaling. Dysfunction of multiple aspects of this is seen in many
cancer phenotypes.

2.3 VDR Transcriptional Networks in Malignancy

Defining the mechanisms by which the VDR exerts desirable anticancer effects has
been an area of significant investigation since the early 1980s. In 1981,
1a,25(OH) D was shown to inhibit human melanoma cell proliferation signifi-
2 3
cantly in vitro at nanomolar concentrations [115], and was subsequently found to
induce differentiation in cultured mouse and human myeloid leukemia cells [116,
117]. Following these studies, anti-proliferative effects have been demonstrated in
a wide variety of cancer cell lines, including those from prostate, breast, and colon
[118–125]. To identify critical target genes that mediate these actions, comprehen-
sive genome-wide in silico and transcriptomic screens have analyzed the anti-pro-
liferative VDR transcriptome and revealed broad consensus on certain targets, but
has also highlighted variability [118, 126–128]. This heterogeneity may in part
reflect experimental conditions, cell line differences, and genuine tissue-specific
differences of cofactor expression that alter the amplitude and periodicity of VDR
transcriptional actions.