Identification of Androgen Receptor and Beta-Catenin Target Genes in Prostate and Prostate Cancer
Annual summary 30 Sep 2012-29 Sep 2013
WASHINGTON UNIV ST LOUIS MO
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The biological role of -catenin in prostate cancer is largely not known. The overall objective of this proposal is to determine the biological significance of androgen receptor AR and -catenin crosstalk in prostate, prostate cancer, and castration resistant prostate cancer cells by identifying their transcriptional targets. These studies demonstrate that -catenin can promote proliferation, survival and adhesion in prostate cancer cells, and this dependence on -catenin may increase with prostate cancer progression. The -catenin inhibitor iCRT-3 was a potent inhibitor of -catenin, the AR- -catenin complex, proliferation, survival and adhesion in prostate cancer cells. Wnt, androgen, or treatment with other growth factors could only partially rescue a subset of these phenotypes. -catenin can interact with other steroid receptors, such as ER , in cervical cancer cells. iCRT-3 can also inhibit cell proliferation and survival in cervical cancer cells and can partially inhibit the -catenin-ER complex, but Wnt treatment can fully rescue. Lastly, Split DamID constructs have been made and conditions optimized to determine the -catenin, AR, and AR- -catenin complex targets in prostate and prostate cancer cells. A new - catenin response element in the proximal PSAKLK3 promoter was discovered. Split DamID data suggests that both AR and -catenin are binding this new response element. This will be confirmed and the biological significance established in future studies.
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