P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription. AR S81 is also phosphorylated by CDK1, and blocking basal CDK1-mediated S81 phosphorylation markedly suppresses AR activity and initiation of this positive feedback loop. Finally, androgen-independent AR activity in castration-resistant prostate cancer (CRPC) cells is driven by increased CDK1-mediated S81 phosphorylation. Collectively these findings reveal a mechanism involving PP1α, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC.

Study Type – Prognosis (case series)
Level of Evidence 4 OBJECTIVE To describe the histological findings and prognosis that are associated with extraprostatic extension (EPE) on needle core biopsy of prostatic adenocarcinoma. PATIENTS AND METHODS We retrieved 99 cases of prostatic adenocarcinoma with EPE at initial diagnosis on biopsy from the consultation files of one of the authors between 1997 and 2009. The 72 cases that had available clinical follow‐up data formed the basis of this study. RESULTS The mean (range) age of the patients was 64 (48–87) years, the median (mean, range) serum prostatic specific antigen level was 7.8 (64.8, 0.3–1505) ng/mL, and 60 of the patients (83%) had abnormalities on a digital rectal examination. The mean (range) number of malignant cores was 7.7 (1–23); the mean percentage of carcinoma in each core was 69.6%, and that in the core(s) with EPE was 76.8%. The mean Gleason score in the core(s) with EPE was 8, with a mean highest Gleason score per case of 8.4. Perineural invasion was detected in 54 cases (75%). Ten of 11 patients treated surgically had EPE on the radical prostatectomy (RP) specimen; also six had positive resection margins, five showed invasion into the seminal vesicles and one had lymph node metastasis. The Gleason scores in nine of the RP specimens did not differ from the highest grade found in the associated biopsies (score 9 in three, 8 in two, 7 in four); in one case it increased (from score 6 to 8) and in one it decreased (from score 9 to 8). Patients were followed for a mean (median, range) of 2.9 (2, 0.1–9) years, with metastases identified in 29 (40%); 10 (14%) died from the disease. CONCLUSION EPE on needle core biopsy of the prostate is strongly associated with extensive, high‐grade prostatic adenocarcinoma, such that its usefulness as an isolated prognostic factor is relatively limited.

Cancer is a significant cause of morbidity and mortality in recipients of renal transplantation. The vast majority develop from recipient origins, whereas donor-derived malignancies are exceedingly rare. We report 2 cases of poorly differentiated donor-derived urothelial carcinoma (UC) in renal transplantation recipients. The first patient underwent a living-related-donor renal transplantation 24 years prior and presented with back pain, hematuria, and rising creatinine and was found to have a 14 cm mass in the renal allograft with regional lymphadenopathy and liver metastases. Pathology showed UC with small-cell differentiation. The second patient presented with hematuria and rising creatinine and was initially found to have muscle invasive bladder cancer seven years after a deceased donor renal transplantation. Nine months after radical cystectomy, a large 9 cm mass was found on his allograft, for which radical nephrectomy and excision of prior ileal conduit was performed. Pathology showed UC with sarcomatoid differentiation. Short tandem repeat (STR) genotyping confirmed donor-derived origins. Both patient tumors expressed PD-L1 suggesting an additional therapeutic avenue for these rare tumors.