Abstract 1507: Fatty acid oxidation mediated autophagy regulation in triple negative breast cancer

Abstract

Abstract Compared to hormone regulated/responsive (ER+) breast cancer (BC), triple negative BC (TNBC) patients have a worse overall survival, a significantly shorter disease-free survival, and a shorter post-recurrence survival. Using transmitochondrial cybrid (cybrid) (compares different mitochondria under a common defined nuclear background)-based discovery and validation in cell lines, patient derived xenografts (PDXs) and BC clinical tissues/data, we recently published that fatty acid oxidation (FAO) is a major energy pathway in TNBC. We also showed that FAO is a major regulator of Src activation by autophosphorylation at Src Y419 in metastatic TNBC. Our data suggest that inhibition of FAO induce cell growth inhibition. Short-term treatment of FAO inhibitors induces both cell cycle arrest and apoptosis. We observed cell cycle arrest in G1-S phase in FAO inhibitor treated TNBC cells. Apoptotic markers like cleaved Caspase-3 and cleaved PARP induced in FAO inhibited cells. Short-term treatment of FAO inhibitor also showed induction of AKT pathway. Further analysis on the role of FAO in TNBC suggests that FAO is a critical player in autophagy signaling in TNBC. Long-term treatment with FAO inhibitors or knockdown of FAO rate-limiting proteins carnitine palmitoyltransferase I (CPT1) induce autophagic cell death with beclin-1 and LC3-II induction in TNBC. However, no such phenomenon observed in estrogen receptor positive (ER+) breast cancer cell lines. Treatment with autophagy inhibitor 3-methyladenine (3-MA) abolished the FAO-induced cell growth inhibition and reduced beclin-1 and LC3-II induction. Ongoing studies using knock-down and over expression approaches focus on the role of specific pathways that are responsible for mitochondrial energy reprogramming regulated autophagy signaling in metastatic TNBC. Citation Format: Kwang Hwa Jung, Jun Hyoung Park, Tirupataiah Sirupangi, Sajna Vithayathil, Lee-Jun Wong, Benny A. Kaipparettu. Fatty acid oxidation mediated autophagy regulation in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1507. doi:10.1158/1538-7445.AM2017-1507