The regulation and function of the estrogen receptor alpha (ERα) by the ligand estrogen (ES) in ovarian tumorigenesis is not well established. Expression of ERα in ovarian carcinoma, like breast carcinoma, is regulated epigenetically and also via changes in growth-factor receptor signaling and intracellular signaling pathways, such as the Mitogen-activated Protein Kinase (MAPK). Numerous studies have documented an inverse relationship between MAPK activity and ERα expression. Oncogenic MAPK signaling can occur via mutation of K-RAS and B-RAF, which are not prevalent in ovarian carcinomas, and overexpression of receptor tyrosine kinases such as HER2. The aim of these studies were to elucidate (i) the relationship between MAPK signaling and ERα expression, in a panel of ovarian carcinoma cell lines and (ii) the utility of PD0325901, a selective allosteric inhibitor of MEK1/2, in sensitizing ERα expressing ovarian cancer to antiestrogen therapy.

We compared ERα expression in a panel of 5 ovarian carcinoma cell lines (A2780, Hey, SKOV3, OVCAR8, IGROV) under physiologic and ES deprived conditions and also after treatment with PD0325901 by immunoblot analysis. The proliferation rate of all cell lines was reduced in E2-free conditions and the PI3K mutant SKOV3 cell line was most sensitive to ES deprivation. A2780 and SKOV3 (PTEN null and PIK3CA mutant, respectively) expressed ERα. The PTEN and BRCA1-null IGROV cells were MEK-dependent and hypersensitive to PD0325901, whereas SKOV3 cells were highly resistant, due to increased phosphorylation and cross-activation of HER2 by PD0325901. Unlike our previous studies in lung cancer, constitutive activation of PIK3CA /AKT did not predict resistance to MEK-inhibitors. Treatment of SKOV3 cells with PD0325901 was associated with increased expression of ERα and altered mobility by immunoblot analysis. These effects were not observed in A2780 cells that express low levels of ERα. Finally, the interaction of the estrogen receptor antagonist fulvestrant and PD0325901 was also evaluated in ERα expressing SKOV3 and A2780 cells. A greater than additive cytotoxic effect was observed in SKOV3, while an antagonistic / minimally additive interaction was noted for A2780 cells that do not show changes in ERα expression after treatment with PD0325901.

Our data support the utility of MEK-inhibitors as modulators of ERα expression and function in ovarian cancer cell lines. Ongoing studies will focus on delineating the mechanism of PD0325901-mediated changes in ERα in various histological subtypes of ovarian carcinoma (such as the clear cell carcinoma cell line SKOV3). This may identify subsets of ovarian cancers that may benefit from therapeutic intervention by estrogen antagonists in conjunction with MEK inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4152.