Importance of steroid receptors and aromatase activity in the prognosis of ovarian cancer: High tumor progesterone receptor levels correlate with longer survival

Slotman, Ben J.; Kühnel, R; Rao, B. Ramanath; Dijkhuizen, G.H.; Graaff, J. de; Stolk, J.

doi:10.1016/0090-8258(89)90607-0

Cited by 48 publications

(15 citation statements)

References 30 publications

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“…There is a higher risk of ovarian cancer in post menopause, at which time androgens are the primary steroids secreted by the ovary [18]. High expression of PR is associated with good prognosis in multivariant analysis for ovarian cancer [19]. However, the results are controversial for the correlation of these three receptors with prognosis and survival rate in patients [12], [20].…”

Section: Introductionmentioning

confidence: 99%

Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer

et al. 2011

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Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR) and estrogen receptor (ER) in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer

et al. 2011

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“…Aromatase inhibitors (AI) reduce estrogen production in post menopausal women by more than 90%. Aromatase expression, analyzed as either aromatase activity, mRNA expression or protein levels, has been found in 33–81% of ovarian cancers [77;78] This wide variability in aromatase detection results from small study size (average 20–40 specimens per study) and different methods used to measure activity (activity assays and mRNA). Aromatase is expressed in ovarian cancer epithelial cells, and in nearby stroma where there is frank ovarian cancer invasion [78;79].…”

Section: Aromatase Expression and Effects Of Aromatase Inhibitors In Ovmentioning

confidence: 99%

New insights on the role of hormonal therapy in ovarian cancer

2013

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Ovarian cancer (OVCA) is the most lethal gynecological malignancy. It is often diagnosed in advanced stages and despite therapy, 70% relapse within 2 years with incurable disease. Regimens with clinical benefit and minimal toxicity are urgently needed. More effective hormonal therapies would be appealing in this setting. Estrogens (E2) are implicated in the etiology of OVCA. Estrogens drive proliferation and anti-estrogens inhibit ovarian cancer growth in vitro and in vivo. Despite estrogen receptor (ER) expression in 67% of OVCAs, small anti-estrogen therapy trials have been disappointing and the benefit of hormonal therapy has not been systematically studied in large well-designed trials. OVCAs often manifest de novo anti-estrogen resistance and those that initially respond invariably develop resistance. Estrogens stimulate ovarian cancer progression by transcriptional activation and cross talk between liganded ER and mitogenic pathways, both of which drive cell cycle progression. Estrogen deprivation and estrogen receptor (ER) blockade cause cell cycle arrest in susceptible OVCAs by increasing the cell cycle inhibitor, p27. This review summarizes and discusses scientific and epidemiological evidence supporting estrogen’s role in ovarian carcinogenesis, provides an overview of clinical trials of ER blockade and aromatase inhibitors in OVCA and reviews potential causes of antiestrogen resistance. Anti-estrogen resistance was recently shown to be reversed by dual ER and Src signaling blockade. Blocking cross-talk between ER and constitutively activated kinase pathways may improve anti-estrogen therapeutic efficacy in OVCA, as has been demonstrated in other cancers. Novel strategies to improve benefit from anti-estrogens by combining them with targeted therapies are reviewed.

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“…For example, Slotman et al (21) observed that there was no correlation between ER expression and overall patient survival in a group of women with ovarian carcinoma, whereas other authors have argued that combined ER/PR expression can distinguish between groups of patients with markedly different survivals (20). Even when used to gauge potential response to hormonal antagonistic therapies, receptor positivity correlates poorly with treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

Molecular clustering based on ERα and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum

et al. 2011

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Assessment of estrogen receptor expression by immunohistochemistry has yielded inconsistent results as a prognostic indicator in ovarian carcinoma. In breast and endometrial carcinomas, panels of estrogen-induced genes have shown improved prognostic capability over the use of estrogen receptor immunohistochemistry alone. For both breast and endometrial cancer, over-expression of estrogen-induced genes is associated with better prognosis. We hypothesized that analysis of a panel of estrogen-induced genes can predict outcome in ovarian carcinoma and potentially differentiate between tumors of varying hormonal responsiveness. From a cohort of 219 women undergoing ovarian cancer surgery from 2004 −2007, 83 patients were selected for inclusion. All patients had advanced stage ovarian/primary peritoneal high-grade serous carcinoma and underwent primary surgical debulking followed by adjuvant treatment with platinum and taxane agents. The expression of ERα and six genes known to be induced by estrogen in the female reproductive tract (EIG121, sFRP1, sFRP4, RALDH2, PR, IGF-1) was measured using qRT-PCR. Unsupervised cluster analyses were used to categorize patients as high or low gene expressors. Gene expression results were then compared to those for estrogen receptor immunohistochemistry. Clusters were compared using chi-square analyses, and Cox proportional hazards were used to evaluate survival outcomes. Median follow-up time was 38.7 months (range 1–68). A cluster defined by EIG121 and ERα segregated tumors into distinct groups of high and low gene expressors. Shorter overall survival was associated with high gene expression (HR 2.84 [1.11–7.30], p=0.03), even after adjustment for other covariates. No difference in estrogen receptor immunohistochemistry expression was noted between gene clusters. In contrast to other hormonally-driven cancers, high expression of ERα and the estrogen-induced gene EIG121 predicts shorter overall survival in patients with high-grade serous ovarian carcinoma. Such a biomarker panel may potentially be used to guide management with estrogen antagonists in this patient population.

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Importance of steroid receptors and aromatase activity in the prognosis of ovarian cancer: High tumor progesterone receptor levels correlate with longer survival

Cited by 48 publications

References 30 publications

Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer

Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer

New insights on the role of hormonal therapy in ovarian cancer

Molecular clustering based on ERα and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum

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