ANNEXIN-A1, A NOVEL BIOMARKER PREDICTS CHEMO-SENSITIVITY TO PPAR-¿ AGONIST THERAPY IN TRIPLE-NEGATIVE BREAST CANCER

Abstract

Chemotherapy is standard of care for treating cancer and controlling tumor progression. However, chemotherapeutic drugs can display a multitude of side effects. An ongoing challenge is to find improved methods of identifying and classifying groups of tumors with differing biological behaviors or responsiveness to specific therapies. Briefly, our observation in model cell lines of TNBC and microarray from TNBC patients reveals significant positive correlations between expression of Annexin A1 (ANXA1) and nuclear receptor, PPAR-gamma. Prompted by this observation, we show activation of PPAR-gamma leads to increased expression of ANXA1 in TNBC model cell lines and in mouse xengraft model. This increased ANXA1 expression is shown to be receptor dependent. Furthermore, we show this increased ANXA1 expression improves chemosensitivity to PPAR-gamma ligands, via increased ANXA1 interaction with the ¿death switch¿ RIP1 leading to caspase-8-dependent apoptosis cascade. The mechanism for induction of RIP1 death pathway is also shown to be an ANXA1-dependent RIP1 deubiquitination coupled with an ANXA1-dependent degradation of a key E3 ligase for RIP1 ubiquitination. Our study therefore provides new preclinical with mechanistic insight for the suitability of using baseline expression ANXA1 and PPAR-gamma as inclusion criteria in PPAR-gamma chemotherapy trials.