Page 38 - Vitamin D and Cancer

Chapter 2
The Molecular Cancer Biology of the VDR

James Thorne and Moray J. Campbell

Abstract The development of an understanding of the role the vitamin D receptor
(VDR) endocrine system plays to regulate serum calcium levels began approxi-
mately three centuries ago with the first formal descriptions of rickets. The parallel
appreciation of a role for the VDR in cancer biology began approximately 3 decades
ago and subsequently a remarkable increase has occurred in the understanding of its
actions in normal and malignant systems.
Principally, much of this understanding has focused on understanding the extent
and mechanism by which the VDR influences expression of multiple proteins
whose combined actions are to govern cell cycle progression, induce differentia-
tion, and contribute to the regulation of programmed cell death, perhaps in response
to loss of genomic integrity. Predominantly, although not exclusively, these
increases in target proteins reflect the transcriptional control exerted via the VDR.
Reflecting the expanding understanding of how chromatin architecture is sensed
and altered by transcription factors, the actions of the VDR have been defined
through the large transcriptional complexes it is found in. The diversity of these
complexes is large, and presumably underpins the pleiotropic biological actions
that the VDR is associated with. The VDR is neither mutated nor deleted in malig-
nancy but instead polymorphic variation distorts its ability to function, as indeed
does expression of a number of associated cofactors, thereby skewing the ability to
transactivate target genes.
Exploitation of this understanding into cancer therapeutic settings may occur
through several routes, but perhaps a more systems orientated approach may yield
insight by identifying and modeling points where the VDR, and closely related
nuclear receptors, exert the most dominant control over cellular processes such as
cell cycle control.

M.J. Campbell (*)
Department of Pharmacology & Therapeutics,
Roswell Park Cancer Institute,
Elm & Carlton Streets, Buffalo, NY 14263, USA
e-mail: Moray.Campbell@RoswellPark.org

D.L. Trump and C.S. Johnson (eds.), Vitamin D and Cancer, 25
DOI 10.1007/978-1-4419-7188-3_2, © Springer Science+Business Media, LLC 2011