Abstract LB-269: Activation of energy sensor AMP-activated protein kinase by rosiglitazone: A novel means to rescue triple-negative breast cancer cells from metastasis

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: A recent epidemiological study reported that triple-negative (TN) breast cancers occurred in association with obesity, which itself has been associated with increased risk for breast cancer. Obesity was present in 49.6% of patients with TN cancer but only in 35.8% of those with non-TN cancer. Considering the increasing epidemic of obesity this 13.8% increase is highly significant. Molecular effects of obesity on breast cancer growth and metastasis are mediated by dysregulation of adipocytokines, leptin and adiponectin. Our lab has previously shown that increased leptin signaling increases breast cancer metastasis whereas another adipocytokine, adiponectin inhibits metastatic potential of breast cancer cells. In the present study, we investigated the potential of thiazolidinediones (TZD) as adiponectin-mimetic in breast carcinogenesis and metastasis. Methods: TN breast carcinoma cell lines, MDA-MB-231 and MDA-MB-468, were used to study the effects on TZDs on TN breast cancer cell viability, anchorage-dependent tumor growth and anchorage-independent growth using the XTT colorimetric assay, clonigenecity assays, and soft-agar assays, respectively. Cell migration (wound-healing) assays were performed to assess the effects of TZDs on cell motility. Reverse-transcription polymerase chain reaction (RT-PCR) and immunoblotting were used to detect mRNA and protein expression levels in TZD treated cells, respectively. Results: Various Thiazolidinediones (TZD) have been developed including Rosiglitazone (RZG), Troglitazone (TGZ), and Pioglitazone (PZG). We found that rosiglitazone (RZG), a novel class of TZD increases adiponectin levels in TN breast cancer cells. We show that RGZ inhibits cell proliferation, anchorage-dependent and -independent growth of TN breast cancer cells in a dose-dependent manner. The ability of a cancer cell to migrate is an essential prerequisite for metastasis. Importantly, RZG treatment inhibits migration potential of TN breast cancer cells. Further examination of the underlying molecular mechanisms revealed that RGZ treatment increases phosphorylation of energy sensor AMP-activated protein kinase in TN breast cancer cells. Increased phosphorylation of AMPK increases its activity as evident by activation of its downstream target, ACC. Intriguingly, we discovered that RGZ treatment also decreases the activation of p-S6K indicating mTOR inhibition. Using AMPK-WT and AMPK-null fibroblasts, we further show that AMPK is required for RZG-mediated inhibition of metastatic potential of TN breast cancer cells. Conclusions: Our studies show that inhibition of metastatic properties of TN breast cancer cells by RGZ involves increased adiponectin levels, elevated AMPK (pAMPK) expression and activity. Our study suggests that RGZ can be used as a novel therapeutic agent for the treatment of aggressive, metastatic TN breast tumors that are unresponsive to current therapeutic regiments. 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-269.