The regulation of growth and protein expression by estrogen in vitro: A study of 8 human ovarian carcinoma cell lines

Leung

Journal of Endocrinology

et al. 2014

Ovarian cancer cells express both estrogen receptor a (ERa) and ERb, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERa compared with ERb, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.

Section: Discussionsupporting

confidence: 82%

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

Leung

Journal of Endocrinology

et al. 2014

Japanese Journal of Cancer Research

“…24) In the present case, PR mRNA expression appeared to be paralleled by protein levels, significant correlations for ERα but not ERβ mRNA expression being evident in both normal and tumor cases. Given the induction of PR after 17β-estradiol treatment in the ER-positive PE04 ovarian carcinoma cell line, 25) our data suggest that ERα may play a central role in the regulation of PR expression in the endometrium.…”

Section: Discussionmentioning

confidence: 99%

Changes in Expression of Estrogen Receptors α and β in Relation to Progesterone Receptor and pS2 Status in Normal and Malignant Endometrium

Saegusa

Okayasu²

2000

Key words: ERα -ERβ -PR -pS2 endometrial carcinomaThe steroid hormone estrogen plays an important role in the growth, differentiation, and function of many target tissues, in particular in the male and female reproductive systems. In the endometrium, hyperestrogenism is considered to the major risk factor for development of malignancy, with or without hyperplastic lesions. 1)Estrogen receptor (ER) α, a member of the superfamily of steroid and thyroid hormone, retinoic acid, and vitamin D receptors, is a ligand-induced transcriptional factor composed of different structural and functional domains.2, 3) The transactivation factor domains (TAF-1 and TAF-2) are located within the NH 2 -terminal (A-B region) and the COOH-terminal (E) sites, whereas the DNA and ligandbinding domains reside in the C and E regions, respectively. Exon 5 deletion splicing of the ER transcript produces a truncated protein which lacks both the TAF-2 and ligand-binding regions, but retains its DNA binding and TAF-1 sequences.4) Previous studies demonstrated that overexpression of the variant is associated with an increase in estradiol-independent growth, resistance to tamoxifen, and enhanced progesterone receptor (PR) expression. 4,5) Recently, a novel ERβ subtype has been discovered in human, rat, and mouse tissues, with a high degree of conservation of the DNA-binding domain (96%), and of the ligand-binding domain (58%), as compared to the amino acid sequence of the ERα protein.6) Although changes in the expression of two ER subtypes have been documented during breast and ovarian tumorigenesis, 7,8) little is known about the endometrial carcinoma case.Several estrogen-inducible genes, including PR and pS2, have been described as markers of estrogen responsiveness in human hormone-dependent tumors. 4,9) In the present study, we investigated the possible contribution of changes in expression of ERα and ERβ at both mRNA and protein levels during endometrial tumorigenesis. The results were also compared with PR and pS2 status, and several clinicopathological factors. MATERIALS AND METHODSCases A total of 48 endometrial carcinomas (endometrioid type), surgically resected at the Kitasato University Hospital during the period from 1995 to 1998, were investigated for mRNAs. Forty normal endometrial samples (17 cases with a regular menstrual cycle and 23 postmenopausal cases) obtained by total hysterectomy for nonmalignant diseases were also examined. Tissues were snap-frozen immediately after surgical excision and stored at −80°C until use. Histological diagnosis was performed according to the criteria of the International Federation of Gynecology and Obstetrics (FIGO). The carcinoma cases comprised 29 grade (G) 1, 13 G2, and 6 G3 lesions.

“…Estrogen regulation of protein expression has been well documented in breast cancer models but to date little is known about estrogen-regulated gene expression in ovarian cancer. Genes which have been shown to be regulated, thus far, include c-myc (Chien et al 1994, Hua et al 1995, progesterone receptor (Nash et al 1989, Langdon et al 1994b, cathepsin D (CTSD) (GaltierDereure et al 1992, Rowlands et al 1993, fibulin-1 (Clinton et al 1996, Moll et al 2002 and insulin-like growth factor binding proteins (Krywicki et al 1993). …”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor-α mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen

O’Donnell¹,

MacLeod²,

Burns³

et al. 2005

Endocr Relat Cancer

136

131

Estrogens play a significant role in the development, growth, invasion and metastasis of ovarian tumors. The transcriptional program regulated by 17b-estradiol (E 2 ) in human ovarian cancer cell lines was analyzed using cDNA microarrays containing 1200 cancer-related genes. Twenty-eight transcripts had at least a threefold change in expression in E 2 -treated PEO1 ovarian carcinoma cells compared with controls. These differences were confirmed by real-time quantitative PCR and shown to be dependent upon the expression of functional estrogen receptor-a (ERa). Consistent with this, these gene expression changes were blocked by the anti-estrogen tamoxifen. The use of ERa-and ERb-specific ligands allowed molecular dissection of the E 2 response and showed that ERa activation was responsible for the observed changes in gene expression, whereas ERb played no significant role. Inhibition of de novo protein synthesis by cycloheximide was used to distinguish between primary and secondary target genes regulated by E 2 . Actinomycin D was used to show that changes in gene expression levels induced by E 2 were a result of changes in transcription and not due to changes in mRNA stability. The results presented here demonstrate that estrogen-driven growth of epithelial ovarian carcinoma is mediated by activation of ERa-mediated, and not ERbmediated, transcription.