Abstract LB-488: Induction of autophagy by heat shock factor 1 promotes breast cancer resistance to chemotherapy

Abstract

Abstract Breast cancer is the most common type of cancer as well as one of the leading causes of cancer-related deaths in women. The increasing emergence of drug resistance to commonly used chemotherapeutic agents has warranted the development of novel and robust treatment options for cancer patients. Carboplatin, a DNA damaging agent, is one of the therapeutic agents which has shown promising results in breast cancer clinical trials. Carboplatin is a second generation platinum drug, increasingly used in clinic to treat cancer patients because of its reduced toxicity and side effects when compared to Cisplatin. Heat Shock Factor 1 (HSF1) is the master regulator of heat shock responses which has also been shown to regulate certain non-heat shock reponse genes. As a transcription factor HSF1 can function as both an activator and repressor of its target genes, resulting in regulation of critical cellular processes invovled in managing cellular stress. The focus of this study is to identify the role of HSF1 in Carboplatin mediated-sensitivity in breast cancer cells, to provide novel insights to improve treatment strategies for cancer patients. Carboplatin treatment in multiple breast cancer cell lines induced growth inhibition which was significantly enhanced upon HSF1 knockdown. Interestingly, the treatment also induced autophagy in these cells. Autophagy is a type II programmed cell death, which is induced in response to metabolic stress and has been demonstrated to mediate drug resistance, since it can play a protective role and allow cells to survive under stressful conditions. Knockdown of HSF1 along with inhibition of autophagy by 3-Methyladenine (3-MA) led to increase in apoptosis in these cells. Furthermore, HSF1 was required for the induction of autophagy in Carboplatin treated cells. Knockdown of HSF1 by siRNA (transient) and shRNA (stable), inhibited induction of autophagy in the presence of Carboplatin, as measured by the punctate EGFP-LC3 structures as well as acridine orange staining. Chromatin immunoprecipitation (ChIP) assay along with Real time- PCR analysis revealed that HSF1 can regulate autophagy by directly regulating the expression of autophagy related genes in the presence of Carboplatin. These findings indicate that HSF1 activates autophagy in response to the Carboplatin induced cellular stress thus leading to cell survival and reducing sensitivity to Carboplatin. Our data strongly support a critical role for HSF1 in promoting chemoresistance through induction of autophgy. This finding has important implications in the development of targeted therapeutics for overcoming Carboplatin resistance in breast cancer. 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 LB-488. doi:1538-7445.AM2012-LB-488