Abstract P4-06-13: Effects of Statin on triple-negative breast cancer (TNBC) with Ets-1 overexpression
Authors: S Lee, HH Jung, YH Park, JS Ahn, Y-H Im
Journal: Cancer Research (2012)

Abstract Background: Triple negative breast cancer (TNBC) is diagnosed accounting for approximately 15–20% of all breast cancer diagnoses and an aggressive clinical phenotype characterized by lack of expression of estrogen receptor (ER) and progesterone receptor (PR) as well as the absence of human epidermal growth factor receptor-2 (HER-2) overexpression. Because of its expression profile, TNBC is not amenable to treatment with hormone therapy or the anti-HER2 monoclonal antibody trastuzumab, and systemic treatment options are limited to cytotoxic chemotherapy. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in TNBC. The proto-oncogene Ets-1 is a member of the Ets family of transcription factors which share a unique DNA binding domain, the Ets domain. Ets proteins are targets for phosphorylation in response to stimulation by a variety of different growth modulators, including intracellular calcium, activators of protein kinase C pathways, growth factors and cytokines. The importance Ets genes in human carcinogenesis is supported by the observations that Ets genes have altered expression patterns, are chromosomally amplified or deleted, or are located at translocation breakpoints in leukemia and solid tumors. In model systems, increased expression of Ets-1 was found to be associated with enhanced angiogenesis and the invasive phenotype. Studies in breast cancer cell lines have implicated Ets-1 in the progression of breast cancer. The present study was conducted to better understand the molecular mechanisms underlying statin-induced suppression associated with transcription factor Ets-1 overexpressed TNBC. Methods: We evaluated the anti-tumor effects of simvastatin on TNBC cells using a MTT assay, invasion assay, siRNA transfection, western blotting and xenograft study which were used to address the role of Ets-1 activity and the Erk/Akt pathway on the effect of simvastatin. Results: We demonstrated that the expression of Ets-1 was increased particular in TNBC cells among various breast cancer cell lines and the simvastatin statistically significantly enhanced antitumor activity in Ets-1 overexpressed TNBC cells. In a mouse model, the growth of Ets-1 expressed TNBC xenograft tumors was statistically significantly inhibited when simvastatin was treated. Furthermore, our data demonstrated for the first time that simvastatin inhibited the growth of TNBC cells by inhibiting Ets-1 activity via Erk and Akt pathway in a dose-dependent manner. Conclusion: Our results suggest that the inhibition of Ets-1 acitivity via Erk and Akt pathway may be a novel mechanism by which simvastatin suppresses the growth of TNBC cells. The ability of simvastatin to induce cell death via Ets-1, as well as its ability to downregulate signaling through Ras/Raf/MEK/Erk and PI3K/Akt pathway, suggested translational value. Exploitation of this activity might include a combination of Ras/Raf/MEK/Erk or PI3K/Akt/mTOR inhibitors and simvastatin to induce cell death or the combination of simvastatin in these signaling pathways. Further preclinical and clinical studies are warranted to further investigate the application of simvastatin for the treatment of TNBC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-13.