Expression of human estrogen receptor-α and -β, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells

Abstract

Our understanding of the roles played by sex hormones in ovarian carcinogenesis has been limited by a lack of data concerning the mode of sex hormone action in human ovarian surface epithelial (HOSE) cells, the tissue of origin of >90% of ovarian cancers. We have compared the relative abundance of estrogen receptor (ER)␣, ER␤, progesterone receptor (PR), and androgen receptor (AR) mRNA in four primary cultures of HOSE cells obtained from postmenopausal women to those found in late serous adenocarcinoma primary cell cultures and established ovarian cancer cell lines. We observed coexpression of ER␣ and ER␤ mRNA along with AR and PR transcripts in normal HOSE cells and disruption of ER␣ mRNA expression as well as dramatic down-regulation of PR and AR transcript expression in most ovarian cancer cells. In contrast, levels of ER␤ mRNA were unaffected by the malignant state. Additionally, a novel mutation involving a 32-bp deletion in exon 1 of ER␣ transcripts was detected in the SKOV3 cell line. This mutation would explain why SKOV3 was reported to be ER-positive but estrogen-insensitive. Taken together, these findings suggest that estrogens, signaling via either or both ER subtypes, may play an indispensable role in regulating normal HOSE cell functions. Therefore, loss of ER␣, PR, and AR mRNA expression in HOSE cells may be responsible for neoplastic transformation in this cell type. In contrast, the roles played by ER␤ in normal and malignant HOSE cells remain elusive. Finally, the coexistence of mutated ER␣ mRNA and normal ER␤ transcripts in SKOV3 argues in favor of a dependency of ER␤ action on functional ER␣s.

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

“…Receptor subtype status of SKOV3 had been controversial in the literature. SKOV3 was reported to be ERa-negative and ERb-positive (Treeck et al 2006) and it had also been described as estrogenunresponsive because it expresses a dysfunctional ERa and very low levels of ERb (Jones et al 1994, Lau et al 1999. However, we demonstrated by western blotting that SKOV3 expressed both receptors, although the expression of ERa was higher than that of ERb in the ratio of 57:1 by quantitative real-time PCR, which is compatible with the findings of O'Donnell et al (2005) and we demonstrated that this cell line was responsive to estrogen.…”

Selenium binding protein 1 in ovarian cancer

“…Androgen receptors are expressed in the surface epithelia of ovary and most ovarian cancers, [27][28][29] and androgen has been suggested to be a risk factor for ovarian cancer. 19 Antiandrogen can inhibit the growth of ovarian cancer cells.…”

Transforming Growth Factor-β1, Transforming Growth Factor-β2, and Transforming Growth Factor-β3 Enhance Ovarian Cancer Metastatic Potential by Inducing a Smad3-Dependent Epithelial-to-Mesenchymal Transition

“…The OVCA429 late-stage serous adenocarcinoma cell line, a generous gift from Dr. M. Sharon Stack (Northwestern University), was cultured as previously described (40). For all experiments, cells were cultured to 80% confluency and serumstarved for 24 h before treatment with 10 ng/mL human TGFh1, TGF-h2, TGF-h3 (R&D Systems) or activin A, purified in our laboratory (41) for 72 h. For transient transfections, cells were plated in complete media and cultured overnight before transfecting with siGENOME SMARTPOOL siRNAs (Dharmacon) or Smad3-GFP using LipofectAMINE 2000 Reagent (Invitrogen) according to the manufacturer's instructions.…”