FP41-5 Context-Dependent Interaction of the Androgen Receptor, ETV1 and PTEN Pathways in Mouse Prostate Cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP41-Sex Hormone Receptors in Development, Aging and Cancer: Omics Approaches
Basic
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:05 AM
Room 121 (Moscone Center)

Poster Board MON-359
Jake Emerson Higgins*, Michele Brogley and Diane M Robins
University of Michigan Medical School, Ann Arbor, MI
The androgen receptor (AR) plays a central role in the onset and progression of prostate cancer (PCa), even after androgen ablation therapy.  Overexpression of the cell regulator ETV1 and inactivation of the tumor suppressor PTEN are common somatic events associated with poor prognosis in PCa.  Genomic rearrangements that place the coding region of ETV1 or other ETS family members under the control of an androgen-responsive promoter occur early in PCa, whereas loss of PTEN is a later event.  The interaction of these pathways with each other and with AR is not fully understood.  To test the hypothesis that ETV1 overexpression acts in part by dysregulating normal AR signaling, a prostate-specific ETV1 transgene was introduced into mice previously engineered to express the human AR.  At 24 weeks of age, ETV1-Tg+ mice showed low frequency prostatic intraepithelial neoplasia (PIN), similar to other reports.  Despite modest pathology, striking differences in gene expression were evident by deep sequencing of dorsolateral lobe transcripts (RNA-seq).  In particular, ETV1 strongly antagonized both induction and repression of AR targets, similar to the effects of castration.  Since PTEN inactivation in PCa is a later event associated with disease recurrence, mice lacking one Pten allele (Pten+/-) were crossed with ETV1 transgenics to test whether PTEN inactivation and ETV1 overexpression cooperate in PCa progression.  Pten+/- mice are known to develop PIN but not cancer.  Pten+/- mice aged more than 40 weeks developed higher grade and more frequent PIN regardless of ETV1 transgene presence, but progression to adenocarcinoma occurred only in ETV1-Tg+ mice.  RNA-seq revealed that much of the earlier ETV1 antagonism of AR regulation was abrogated by reduced PTEN, although a modest overall suppression of AR activation occurred.  Moreover, some AR targets that were derepressed in ETV1-Tg+ mice were also elevated in Pten+/-/ETV1-Tg+ prostates, suggesting genes normally repressed by AR are key in cancer progression.  Overall, the Pten+/- expression profile, even prior to significant cancer, resembled castrate-resistant disease, suggesting PTEN loss predisposes androgen independent AR action.  The mechanistic basis by which factors in the PTEN pathway direct AR/ETV1 interaction is currently being investigated in vitro.  ETV1 overexpression in benign prostate cells inhibited induction of AR reporters, supporting a suppressive role of ETV1 on AR signaling in early PCa.

Nothing to Disclose: JEH, MB, DMR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Sources of Research Support: NIH, DOD, NIH NRSA #GM07544 from the NIGMS (JH)