Abstract 4595: ERK/MAPK regulation of ERRγ in Tamoxifen resistant breast cancer

Abstract

Abstract Breast cancer is a serious public health problem that is the second-most common cause of cancer-related death in women. Endocrine therapy, like Tamoxifen (TAM), has made significant contributions to the successful management of ER+ breast cancer but unfortunately 30-50% of these tumors may acquire endocrine resistance. However, not all ER+ breast cancers are the same. Two of the major classifications of breast cancer are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). In comparison to IDC, a significantly greater percentage of ILCs are estrogen receptor alpha-positive (ER+) and progesterone receptor-positive (PR+). Therefore, women diagnosed with this tumor subtype should be ideal candidates for endocrine or antiestrogen therapy. However, clinical studies differ as to whether ILC patients experience better or worse survival following antiestrogen treatment when compared to ER+ IDC patients. In a model of TAM-resistance in ILC, we have shown that the orphan nuclear receptor estrogen related receptor gamma (ERRγ) plays a functional role in the resistant phenotype of LCCTam cells, ERRγ overexpression is sufficient to induce TAM resistance, and we show for the first time that ERRγ is serine-phosphorylated in TAM-resistant breast cancer cells in association with increased expression and activity of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK; ERK). We have also recently found an IDC-derived model of TAM-resistance to overexpress ERRγ. Therefore, we hypothesize that ERK regulates ERRγ transcriptional activity and is a critical determinant of ERRγ-induced TAM resistance in breast cancer. To test this hypothesis, we used two antiestrogen-sensitive and -resistant breast cancer cell line pairs: IDC-derived RR cells and their sensitive controls MCF7, and the ILC-derived LCCTam cells and their sensitive controls SUM44. In both sensitive controls we found TAM alone to cause cell death. When we added the ERK inhibitor, U0126, to the TAM treatments, cell death increased. The resistant cell lines showed no effect with the addition of TAM alone, but the TAM treatment coupled with the inhibitor restored sensitivity and caused cell death. Additionally, we tested the transcriptional activity of ERRγ in the presence or absence of the ERK inhibitor. We found each of the four cell lines to show decreased ERRγ transcriptional activity in the presence of U0126. Future studies include the identification of the serine residues on ERRγ being phosphorylated by ERK, and whether ERRγ overexpression is associated with increased ERK expression and activity, poor overall survival, and poor response to TAM in breast cancer patients treated with endocrine therapy. 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 4595.