17β-Estradiol at Low Concentrations Acts through Distinct Pathways in Normal Versus Benign Prostatic Hyperplasia-Derived Prostate Stromal Cells

Abstract

The aim of this study was to identify differential responses to low concentrations of 17beta-estradiol (E2) in primary stromal cell cultures derived from either normal organ donors or benign prostatic hyperplasia or hypertrophy (BPH) specimens. Furthermore, we sought to identify the potential mechanism of E2 action in these cell types, through either a genomic or nongenomic mechanism. We initially treated stromal cells derived from five normal prostates or five BPH specimens with low concentrations of E2 (0.001-1.0 nM) and analyzed their growth response. To determine whether genomic or nongenomic pathways were involved, we performed studies using specific estrogen receptor antagonists to confirm transcriptional activity or MAPK inhibitors to confirm the involvement of rapid signaling. Results of these studies revealed a fundamental difference in the mechanism of the response to E2. In normal cells, we found that a nongenomic, rapid E2 signaling pathway is predominantly involved, mediated by G protein-coupled receptor-30 and the subsequent activation of ERK1/2. In BPH-derived prostate stromal cells, a genomic pathway is predominantly involved because the addition of ICI 182780 was sufficient to abrogate any estrogenic effects. In conclusion, prostate stromal cells respond to far lower concentrations of E2 than previously recognized or examined, and this response is mediated through two distinct mechanisms, depending on its origin. This may provide the basis for new insights into the causes of, and possible treatments for, BPH.

Estrogens and Prostate Cancer: Etiology, Mediators, Prevention, and Management

“…176 GPR30 has been localized in the cell membrane and endoplasmic recticulum of various estrogen-sensitive tissues and cell lines 176-178 and to mediate the non-genomic action of E2 in breast, endometrial, and ovarian cancer cells through the activation of Erk1/2 and cAMP pathways. 179;180 GPR30 is expressed in the immortalized normal prostate stroma cell line WPWY-1 but does not appear to mediate the growth response induced by high-dose E2. 181 A recent study demonstrated positive staining of GPR30 in both plasma membrane and cytoplasm in the normal and cancerous prostate, and its predominant expression in the luminal epithelium.…”

Role of the Adjacent Stroma Cells in Prostate Cancer Development and Progression: Synergy between TGF-βand IGF Signaling

“…It mediates its action through interaction with estrogen receptor (ER). There are three types of estrogen receptors, ER α , ER β , and GPR30 [70]. ER α and GPR30 promote proliferation, whereas ER β has proapoptotic and prodifferentiating functions [70, 71].…”

“…There are three types of estrogen receptors, ER α , ER β , and GPR30 [70]. ER α and GPR30 promote proliferation, whereas ER β has proapoptotic and prodifferentiating functions [70, 71]. Prostate stromal cells contain mainly ER α and GPR30 [69].…”

Distinct Function of Estrogen Receptor α in Smooth Muscle and Fibroblast Cells in Prostate Development

“…Perhaps more interesting would be the effect of smER␣KO on prostate metastasis due to ER␣'s role in basement membrane integrity. Stromal ER␣ is already implicated in BPH initiation (10). This is especially poignant, because BPH is characterized by an increase in smooth muscle cells (55).…”