Anti-KRT18 monoclonal antibody, clone CY90

Multiple observations suggest a cell type-specific role for TP53 in mammary epithelia. We developed an in vitro assay, in which primary mouse mammary epithelial cells (mMECs) progressed from lumenal to basal-like phenotypes based on expression of Krt18 or Delta Np63, respectively. Such transition was markedly delayed in Trp53(-/-) mMECs suggesting that Trp53 is required for specification of the basal, but not lumenal cells. Evidence from human basal-like cell lines suggests that TP53 may support the activity of Delta Np63 by preventing its translocation from nucleoplasm into nucleoli. In human lumenal cells, activation of TP53 by inhibiting MDM2 or BRCA1 restored the nucleoplasmic expression of Delta Np63. Trp53(-/-) mMECs eventually lost epithelial features resulting in upregulation of MDM2 and translocation of Delta Np63 into nucleoli. We propose that TP63 may contribute to TP53-mediated oncogenic transformation of epithelial cells and shed light on tissue-and cell type-specific biases observed for TP53-related cancers.

IMPORTANCE There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. OBJECTIVES To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. DESIGN, SETTING, AND PARTICIPANTS The PAM50 classifierwas used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal-and basal-like subtypes. MAIN OUTCOMES AND MEASURES Metastasis, biochemical recurrence, overall survival, prostate cancer-specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. RESULTS Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction). CONCLUSIONS AND RELEVANCE Luminal-and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non-luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.