Estrogens represent a under-recognized contributor in CaP development and progression. Further research in this topic may provide opportunities for identification of environmental influencers as well as providing novel therapeutic targets in the treatment of CaP.

Human prostate stem and progenitor cells express estrogen receptor (ER)α and ERβ and exhibit proliferative responses to estrogens. In this study, membrane-initiated estrogen signaling was interrogated in human prostate stem/progenitor cells enriched from primary epithelial cultures and stem-like cell lines from benign and cancerous prostates. Subcellular fractionation and proximity ligation assays localized ERα and ERβ to the cell membrane with caveolin-1 interactions. Exposure to 17β-estradiol (E2) for 15 to 60 minutes led to sequential phosphorylation of signaling molecules in MAPK and AKT pathways, IGF1 receptor, epidermal growth factor receptor, and ERα, thus documenting an intact membrane signalosome that activates diverse downstream cascades. Treatment with an E2–dendrimer conjugate or ICI 182,870 validated E2-mediated actions through membrane ERs. Overexpression and knockdown of ERα or ERβ in stem/progenitor cells identified pathway selectivity; ERα preferentially activated AKT, whereas ERβ selectively activated MAPK cascades. Furthermore, prostate cancer stem-like cells expressed only ERβ, and brief E2 exposure activated MAPK but not AKT cascades. A gene subset selectively regulated by nongenomic E2 signaling was identified in normal prostate progenitor cells that includes BGN, FOSB, FOXQ1, and MAF. Membrane-initiated E2 signaling rapidly modified histone methyltransferases, with MLL1 cleavage observed downstream of phosphorylated AKT and EZH2 phosphorylation downstream of MAPK signaling, which may jointly modify histones to permit rapid gene transcription. Taken together, the present findings document ERα and ERβ membrane-initiated signaling in normal and cancerous human prostate stem/progenitor cells with differential engagement of downstream effectors. These signaling pathways influence normal prostate stem/progenitor cell homeostasis and provide novel therapeutic sites to target the elusive prostate cancer stem cell population.

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Delayed treatment and non-adherence are associated with inferior prostate cancer (CaP) outcomes. Missed clinic appointments (MA) are one form of non-adherence that may be preventable. We conducted a retrospective cohort study of 1341 scheduled clinic encounters for men referred to an academic urology clinic for evaluation of known or suspected CaP. Driving distance and public transit times were calculated using a Google Distance Matrix API algorithm. Zip code level data regarding socioeconomic status was obtained from the 2013 American Community Survey. Logistic regression multivariate analysis was used to identify MA predictors. Of scheduled clinic encounters, 14% were missed. Public health insurance was associated with MA (Private insurance 10%, Public insurance 19%), (p < 0.01) Calendar month was associated with MA with December showing the highest rate (21.2%) and June the lowest (5.3%) rates. (p = 0.02) Appointments for suspected CaP were more likely to be missed (19.3%) than those for known CaP (10.5%), p < 0.01. Driving distance was inversely associated with rate of MA (CA median 11.8 miles, MA median 10.4 miles, p = 0.04) while public transit times were not (66.7 min for CA, 65.3 min for MA, p = 0.36). Men that missed appointments were from areas with lower household incomes and educational attainment. Patient encounter type, insurance status, and reason for referral remained significantly associated with MA after multivariable adjusted analysis. By computing public transit time to the clinic using a mapping engine, we present a novel way to measure this parameter for studies of urban health care.

This pattern of staining raises concern for a possible contributing role of exogenous estrogen therapy in tumorigenesis. As awareness of gender dysphoria and acceptance of gender reassignment surgery has seen a recent increase, the unique needs of this population must be recognized. Prostate 77:824-828, 2017. © 2017 Wiley Periodicals, Inc.