Abstract 166: A novel therapeutic approach for triple negative breast cancer

Abstract

Abstract Triple negative breast cancers (TNBCs) are defined as tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (EGFR2). TNBCs account for 15-20% of all breast tumors. These breast tumors are usually aggressive and have a specific molecular profile. Unfortunately, treatment options for TNBCs are limited, leading to a poor prognosis and high mortality rates. Thus, novel therapeutic approaches are needed to treat TNBCs. To date, several molecular targets have been identified (e.g., PARP, EGFR, mTOR, Akt, and BRAC-1). Moreover, many pre-clinical and clinical trials are underway to determine the efficacy of specific inhibitors against these molecular targets, used either alone or in combination with chemotherapeutic agents. So far, these trials have failed to produce significant promising results. Hence, our goal is to identify novel therapeutic agents that specifically target breast tumor cells, especially TNBCs, without causing toxicity to normal cells. Our studies identified nimbolide as a novel therapeutic agent. Nimbolide is a major bioactive compound derived from the Azadirachta indica (Neem) leaves, which is well-known medicinal plant having a wide spectrum of biological activities. In our studies, nimbolide targeted TNBC cells without causing toxicity to normal primary breast epithelial cells. We also explored the molecular mechanism underlying the anti-cancer effect of nimbolide on TNBC cells and found that nimbolide, simultaneously inhibited phosphorylation of Akt mediates pro-survival signaling. In addition, downstream signaling by mTOR and NF-kappa-B was down regulated by nimbolide which resulted in the induction of pJNK and pc-Jun mediated pro-apoptotic signaling and apoptosis in TNBC cells. These changes in the pro and anti-apoptotic molecular circuits also inhibited migration and invasion properties of TNBC cells. Altogether, our results strongly suggest that nimbolide could be a potent compound for the prevention and/or treatment of TNBC. Our ongoing in vivo studies may reveal the in vivo efficacy of nimbolide and toxicity to other organs or cells if any. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 166. doi:1538-7445.AM2012-166