Differential Actions of Estrogen Receptor α and β via Nongenomic Signaling in Human Prostate Stem and Progenitor Cells

Abstract

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.

The role of estrogen receptor beta in breast cancer

“…Alternations in estrogenic signaling pathways, as well as ERβ expression, have been discussed in the context of physiological and pathological processes, such as maintenance of the bone marrow microenvironment [ 11 ], neuronal-mediated contractions of the gastrointestinal tract [ 12 ], recovery of reproductive system injury [ 13 ], anxiolytic effects [ 14 ], and diseases such as Parkinson’s disease [ 15 ], endometriosis [ 16 ], myocardial infarction [ 17 ] and type 2 diabetes [ 18 ]. Moreover, ERβ has been shown to participate in the pathological process of various cancers, including uterine leiomyomas [ 19 ], colorectal cancer [ 20 ], desmoid tumors [ 21 ], prostate cancer [ 22 ] and duct carcinoma [ 23 ].…”

Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance

“…Human prostate CSCs and papillary thyroid CSCs highly express ERβ (114,115). ERβ overexpression in CSCs can promote cancer stemness through estrogen signaling (91,115). Thus, estrogen can directly regulate CSCs by activating ERβ.…”

“…Although most CSCs are ER − ( 10 , 75 ), estradiol can nevertheless increase the number of CSCs, possibly via the non-genomic signaling pathway, which is a regulatory mechanism that does not involve direct binding to DNA and only occurs in the plasma membrane and cytoplasm ( 66 , 83 , 84 ). The non-genomic estrogen signals that regulate CSCs are mainly mediated by cell membrane–associated ERs, including G protein–coupled ER (GPER/GPR30) ( 85 – 87 ), ERα variant ERα36 ( 88 – 90 ), and ERβ ( 91 ) ( Figure 1 ).…”

Pharmacological Modulation of Steroid Activity in Hormone-Dependent Breast and Prostate Cancers: Effect of Some Plant Extract Derivatives

“…AR is not the only nuclear receptor that could be involved in the progression of PCa. Hence, Gail Prins' group has shown that early exposure to estrogens and estrogen-like compounds could also increase PCa incidence through ERα [30,31].…”