Estrogen action in human ovarian cancer

Clinton, Gail M.; Hua, Wenhui

doi:10.1016/s1040-8428(96)00216-8

Cited by 75 publications

(52 citation statements)

References 68 publications

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“…Monotherapy studies using tamoxifen, aromatase inhibitors, and GnRH analogues had yielded variable results with objective response rates ranging between 0 and 56%. 17,[19][20][21][34][35][36][37][38] Combinatorial treatment regimens combining tamoxifen and goserelin or tamoxifen and Gefitinib had obtained results with objective response rates of up to 11.5%. 39,40 Few of these studies had selected patients based on the immunohistochemically determined estrogen receptor status.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, concerning tamoxifen, it has not been definitely clarified whether it only acts as a pure estrogen antagonist in ovarian tissue, or it has also an agonist effects. [17][18][19][20][21] In breast cancer, we had recently described estrogen receptor-a (ESR1) gene amplification as a frequent mechanism for estrogen receptor overexpression. More than 20% of breast cancers showed ESR1 gene amplification and more than 15% additional cases low-level ESR1 gene copy number gains.…”

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Estrogen receptor gene amplification occurs rarely in ovarian cancer

et al. 2009

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Amplification of the gene encoding estrogen receptor-a occurs in about 20% of breast cancers and is an important mechanism for estrogen receptor overexpression in this tumor type. In ovarian cancer, overexpression of estrogen receptor protein has been described in more than two thirds of cases. To study a potential role of estrogen receptor-a gene amplification for estrogen receptor overexpression in ovarian cancer, a tumor tissue microarray containing 428 ovarian cancers was analyzed by fluorescence in situ hybridization for estrogen receptor-a gene amplification and immunohistochemistry for estrogen receptor expression. The estrogen receptor-a gene status was successfully determined in 243 of 428 arrayed cancers. Estrogen receptor gene amplification was found in 5 of 243 (2%) of tumors. Amplification levels were usually low, with 4-8 estrogen receptor-a gene copies. However, one case had a high-level amplification, with more than 30 estrogen receptor-a gene copies. Keywords: ovarian cancers; estrogen receptor-a gene; estrogen receptors; fluorescence in situ hybridization; immunohistochemistry Worldwide, ovarian cancer is the fifth most frequent malignant tumor in women and the most common cause of death among cancers of the reproductive system.1 Prognosis is generally poor as these cancers are often detected in late stage. The median overall survival in these patients is 24-38 months after diagnosis. 2Treatment options include surgical removal of the tumor mass with a maximal reduction of the peritoneal cancer mass in case of local tumor extension. In addition, topical and systemic cytotoxic therapy is applied. Ovarian cancer belongs to the group of cancers with frequent expression of steroid hormone receptors. Depending on the study estrogen receptor expression has been reported in 25-86% of ovarian cancers with the highest percentages reported in endometroid and serous subtypes.3-16 Accordingly, endocrine therapy is a recognized option in the treatment of chemoresistant ovarian cancer after the failure of first-and second-line therapies. However, not all estrogen receptor-positive ovarian cancers respond to antiestrogen therapy, and it was suggested that it might be because of the facts that most of the studies have been retrospective, small in size without adequate selection of the patients and generally used hormonal therapy as a last-line therapy for the refractory or resistant ovarian cancers. Moreover, concerning tamoxifen, it has not been definitely clarified whether it only acts as a pure estrogen antagonist in ovarian tissue, or it has also an agonist effects. 17-21In breast cancer, we had recently described estrogen receptor-a (ESR1) gene amplification as a frequent mechanism for estrogen receptor overexpression. More than 20% of breast cancers showed ESR1 gene amplification and more than 15% additional cases low-level ESR1 gene copy number gains.22 Preliminary data also suggested that ESR1 amplified breast cancers may exhibit a high responsiveness to tamoxifen. To determine, whether ESR1 amplificat...

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Section: Discussionmentioning

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Estrogen receptor gene amplification occurs rarely in ovarian cancer

et al. 2009

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“…In vitro data demonstrating the proliferative role of estrogen in ovarian cancer cell lines and the in vivo correlation between circulating estrogens and tumor development suggest that ERa likely plays an essential role in ovarian cancer. However, only 15-20% of patients with ERa-positive tumors show a clinical response to anti-estrogens (Clinton & Hua 1997). Given the potential crosstalk between the estrogen-signaling pathway and that of ERRa, it is tempting to speculate that ERRa may be part of the explanation for the common resistance of ovarian cancers to ERa blockade.…”

Section: R Stein and D P Mcdonnell: Erra In Breast Cancermentioning

confidence: 99%

Estrogen-related receptor α as a therapeutic target in cancer

Stein¹,

McDonnell²

2006

Endocr Relat Cancer

102

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The orphan receptor estrogen-related receptor a (ERRa) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERRa as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERRa action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.

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“…[1][2][3][4]. Etiological factors involved in ovarian carcinogenesis remain poorly defined, and effective treatment protocols are limited (1)(2)(3). Epidemiological data suggest that endogenous and exogenous sex hormones may play important roles in the pathogenesis of the disease.…”

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confidence: 99%

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

Lau

Mok

1999

Proc. Natl. Acad. Sci. U.S.A.

256

161

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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.

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Estrogen action in human ovarian cancer

Cited by 75 publications

References 68 publications

Estrogen receptor gene amplification occurs rarely in ovarian cancer

Estrogen receptor gene amplification occurs rarely in ovarian cancer

Estrogen-related receptor α as a therapeutic target in cancer

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

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