Date of Award

1-1-2014

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (vii, 143 pages) : illustrations (some color)

Dissertation/Thesis Chair

JoEllen Welsh

Committee Members

Martin Tenniswood, Doug Conklin, Bruce Herron, Ramune Reliene

Keywords

Breast, Vitamin D, Nuclear receptors (Biochemistry)

Subject Categories

Cell Biology | Genetics | Molecular Biology

Abstract

1,25-Dihydroxyvitamin D (1,25D) exerts anti-cancer actions through the vitamin D receptor (VDR) but the specific targets that mediate these effects remain to be defined. In these studies, growth and genomic responses to 1,25D were evaluated in a cellular model system derived from mammary tumors generated in VDR knockout (KO) and wildtype (WT) mice. WT145 cells (derived from WT tumors) expressed VDR and were growth inhibited by 1,25D, whereas KO240 cells (derived from VDRKO tumors) lacked VDR and were not growth inhibited by 1,25D. KO240 cell clones stably expressing VDR (KOhVDR cells) were sensitized to 1,25D mediated growth arrest. Genomic profiling of KO240, KOhVDR and WT145 cells identified 35 transcripts that were altered by 1,25D prior to growth inhibition. Eight candidate genes were selected for follow-up and qPCR analysis demonstrated that 1,25D significantly up-regulated Cyp24a1, Cib2, Enpp1, and Prelp and down-regulated Plau, Postn, Has2, and Hbegf in WT cells and in KOhVDR cells, but not in KO240 cells. KO240 cells stably expressing hVDRs containing DNA binding domain mutations found in hereditary vitamin D resistant rickets (HVDRR) patients were not growth inhibited by 1,25D or more potent vitamin D metabolites or analogs and were not able to alter gene expression in response to 1,25D.

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