Our observation that PI3K inhibition leads to increased HER3 levels in Ptenlox/lox large-scale peptide synthesis mice MAPK function and in LNCaP cells raises the possibility that human tumors with PTEN loss might have decreased HER2/3 activity. We did not observe significant differences in HER3 mRNA levels, but HER2 expression was significantly reduced in PTEN loss prostate cancers. Furthermore, HER2 expression was significantly correlated with AR target gene signature output. Because other genomic alterations may impact the interpretation of the human tumor studies, we examined AR activity in primary prostate tissue harvested from 8 week Ptenlox/lox mice before the onset of prostate cancer. To define a murine AR gene signature, we first compared transcriptomes of prostates from wild type mice to those from littermates isolated 3 days post castration.

In parallel, we compared transcriptome data from prostates isolated from intact Pten and Pten mice. GSEA revealed that genes up or down regulated in response to castration in wild type mice were significantly enriched in intact Pten prostates compared to intact Plastid Pten+/+ prostates, indicating that Pten loss is associated with reduced AR activity. Examination of individual genes revealed that a substantial number of the genes up or downregulated by castration in intact mice are already up or downregulated in intact Pten mice. Together with the human prostate tumor data and the BEZ235 treatment studies, these findings establish that the increase in PI3K activation associated with PTEN loss impairs AR signaling.

Previous studies ALK inhibitor in mouse models and cell lines have implicated PTEN loss as a potential cause of castration resistance. Our finding that PI3K activation is associated with reduced AR output suggest a potential explanation, e. g. these tumors are less dependent on AR. However, it is possible that AR function, albeit low, remains intact due to low circulating androgens that remain after castration. To investigate the potential role of persistent AR signaling in this context, we evaluated the effect of combined androgen blockade in the Pten model. After 7 days of treatment, mRNA levels of the androgen regulated genes Pbsn, Nkx3. 1, and Psca were decreased 25?50 fold and AR protein levels were primarily cytoplasmic, confirming substantial inhibition of AR pathway output in tumors isolated from treated mice. Despite this magnitude of pathway inhibition, tumors showed only modest regression without obvious histologic changes. In addition, there was minimal effect on proliferation as measured by Ki67 staining. In contrast, the same treatment regimen in PB MYC mice resulted in profound reductions in tumor volume, near complete pathologic responses and virtually absent Ki67 staining.