Investigating Steroid Receptor Coactivator 3 (SRC3) as a Potential Therapeutic Target for Treating Advanced Prostate Cancer
Annual summary rept. 15 Mar 2011-14 Mar 2013
TEXAS A AND M RESEARCH FOUNDATION COLLEGE STATION
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Steroid Receptor Coactivator-3 SRC-3 is a transcriptional coactivator that promotes proliferation of prostate cancer CaP cells. Although SRC-3 is highly expressed in advanced CaP, its role in PTEN deficiency-promoted castration resistant CaP CRPC is unknown. We found elevated SRC-3 in human CRPC and in PTEN-negative human CaP. Patients with high SRC-3 and no PTEN exhibit decreased recurrence-free survival. We generated Pten3CKO mice in which floxed Pten and SRC-3 genes are specifically and concomitantly deleted in prostate epithelial cells PECs. We compared tumor mass, histology and biomarkers in these Pten3CKO mice versus PtenCKO control mice in which only floxed Pten alleles are deleted in PECs. Deletion of SRC-3 impaired cellular proliferation, causing reduced tumor size. Interestingly, castration of PtenCKO control mice significantly increased tumor aggressiveness over time versus their non-castrated counterparts, as indicated by increased proliferation, de-differentiation and reactive stroma. Remarkably, SRC-3 ablation in Pten3CKO mice reversed all the changes comprising this aggressive phenotype. Versus controls, Pten3CKO tumors in castrated mice had decreased phospho-Akt, S6 kinase and phosphorylated S6, which are mediators of cell growth and proliferation. In addition, these tumors seem more differentiated as evidenced by higher levels of Fkbp5, an AR-responsive gene that inhibits Akt signaling. These tumors also had lower levels of some androgen-repressed genes like cyclin E2 and MMP10. These results reveal SRC-3 promotes CRPC by inducing proliferation, de-differentiation, and stromal reactivity possibly through the AktS6K pathway. These features make SRC-3 a putative target for abrogating CRPC progression.
- Medicine and Medical Research