Abstract LB-224: Leptin-induced breast cancer cell migration requires upregulation of antiapoptotic protein, survivin

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Leptin, an adipocytokine secreted by adipose tissue, is responsible for many biological functions including appetite regulation, energy homeostasis, bone formation, and more recently, carcinogenesis. Levels of circulating leptin are typically elevated in obese states and have been associated with increased tumor proliferation, angiogenesis, and increased metastatic behavior. Therefore, obesity has been clearly associated with increased risk of cancer and metastasis. Breast cancer remains as the second leading cause of cancer-related deaths to American women. Many epidemiological studies have shown that obese women are more at risk for developing breast cancer compared to non-obese women. Therefore, it is imperative to understand the contribution of leptin to breast cancer development and progression. Methods and Results: In this study, we used MCF-7 and MDA-MB-231 breast cancer cell lines to examine the relationship between leptin and survivin, a dual-function protein. Survivin has become an interesting target in cancer research because it is highly expressed in cancerous tissues while being nearly undetectable in normal tissues. We observed that leptin increases mRNA and protein expression of survivin in a time-dependent manner. Earlier studies from our lab demonstrated that leptin increases breast cancer cell migration and invasion and underlying mechanisms involved a bidirectional crosstalk between leptin and IGF1 leading to transactivation of EGFR. Examining the underlying mechanisms, we found that blocking EGFR activation decreased leptin-induced survivin expression indicating the involvement of EGFR. To examine the role of survivin in leptin-induced migration of breast cancer cells, we transfected both cell lines with wild-type or p-silencer-survivin and subjected the cells to scratch and electric cell-substrate impedance sensing (ECIS) migration assays. We found that survivin overexpression increased migration potential of breast cancer cells compared to untransfected cells. In addition, leptin treatment further enhanced migration of breast cancer cells with survivin overexpression. Inhibition of survivin inhibited migration of breast cancer cells alone and even in the presence of leptin. These studies showed the importance of survivin in leptin-induced migration of breast cancer cells. For therapeutic purposes, we treated the breast cancer cells with lovastatin, commonly used as an HMG-CoA reducatase inhibitor. Lovastatin has been previously shown to inhibit survivin expression. We treated cells with lovastatin in a dose-dependent manner and observed a complete inhibition of survivin expression. Combination treatment with leptin did not restore survivin protein expression. Importantly, lovastatin treatment efficiently inhibited migration of breast cancer cells even in the presence of leptin. Conclusion: In conclusion, we have established a novel role for survivin in leptin-induced migration of breast cancer cells. Targeting survivin using lovastatin may provide new therapeutic targets for the treatment of metastatic breast carcinogenesis in obese patients. 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 LB-224.