Probes for PTEN

Genetic alterations that potentiate PI3K signalling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/amplification correlates with poor prostate cancer patient survival. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3caH1047R mutation causes p110α-dependent invasive prostate carcinoma in-vivo. Furthermore, we report PIK3CA mutation and PTEN loss co-exist in prostate cancer patients, and can cooperate in-vivo to accelerate disease progressionvia AKT-mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant Pik3ca mutation and Pten loss caused de-novo CRPC. Thus, Pik3ca mutation and Pten deletion are not functionally redundant. Our findings indicate that PIK3CA mutation is an attractive prognostic indicator for prostate cancer that may cooperate with PTEN loss to facilitate CRPC in patients.

Phosphatase and tensin homolog (PTEN) acts as a brake for the phosphatidylinositol 3-kinase-AKT-mTOR complex 1 (mTORC1) pathway, the deletion of which promotes potent central nervous system (CNS) axon regeneration. Previously, we demonstrated that AKT activation is sufficient to promote CNS axon regeneration to a lesser extent than PTEN deletion. It is still questionable whether AKT is entirely responsible for the regenerative effect of PTEN deletion on CNS axons. Here, we show that blocking AKT or its downstream effectors, mTORC1 and GSK3β, significantly reduces PTEN deletion-induced mouse optic nerve regeneration, indicating the necessary role of AKT-dependent signaling. However, AKT is only marginally activated in PTEN-null mice due to mTORC1-mediated feedback inhibition. That combining PTEN deletion with AKT overexpression or GSK3β deletion achieves significantly more potent axonal regeneration suggests an AKT-independent pathway for axon regeneration. Elucidating the AKT-independent pathway is required to develop effective strategies for CNS axon regeneration.

The presence and extent of cribriform pattern of prostate cancer portend recurrence and cancer death. Therelative expressions within this morphology of the prognostically adverse loss of PTEN, and the downstream inactivation of cell cycle inhibitor p27/Kip1 had been uncertain. In this study, we examined 52 cases of cribriform cancer by immunohistochemistry (IHC) for PTEN, p27, and CD44 variant (v)7/8, and a subset of 17 casesby chromogenic in situ hybridization (ISH) using probe for PTEN or CDKN1B (gene for p27). The fractions of epithelial pixels positive by IHC and ISH were digitally assessed for benign acini, high grade prostatic intraepithelial neoplasia (PIN), and 8 morphological patterns of cancer. Immunostaining results demonstrated that: 1. PTEN loss was significant for fused small acini, cribriform-central cells, small cribriform acini, and Gleason grade 5 cells in comparison with other acini. 2. p27 loss was significant only for cribriform-peripheral cells; and borderline-significant for fused small acini in comparison with benign acini. 3. CD44v7/8 showed expression loss in cribriform-peripheral cells; other comparisons were not significant. ISH showed thatcribriform cancer had significant PTEN loss normalized to benign acini (P < .02), while Gleason 3 cancer or fused small acini did not. With CDKN1B, the degree of signal loss among various cancer morphologies was insignificant. In conclusion, molecular disparities emerged between the fused small acini and cribriform patterns of Gleason 4 cancer. PTEN or p27 loss as prognostic factors demand distinct assessment in the varieties of Gleason 4 cancer, and in the biphenotypic peripheral versus central populations in cribriform structures.