Inflammatory breast cancer (IBC) is the most lethal, distinct form of breast cancer, however, the basis for its aggressiveness and rapid acquisition of drug resistance is not fully understood. Using immunohistochemical analysis, we identified a strong correlation between high grade, high stage, and triple-negative status and elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) in IBC. Molecular profiling of multiple IBC cell lines revealed that modulating XIAP expression can significantly alter the expression pattern of a 79-gene, characteristic IBC profile that was previously obtained from clinical samples. Using specific antagonists and RNAi, we determined that the mitogen activated protein kinase (MAPK) pathway and its interaction with the protein synthesis initiation factor eIF4G1, both of which are elevated in IBC, cooperate to drive XIAP induction and resistance to therapeutic apoptosis. Further, we found that XIAP expression directly correlates with activation of the transcription factor NFκB, a molecular component defining IBC. Mutational analysis revealed that the BIR1 domain of XIAP is essential for subsequent TAB1:IKKβ-dependent NFκB activation. After determining this association between XIAP and TAB1, we tested a peptide-mediated strategy used to block the BIR1:TAB1 interaction antagonized NFκB activity which led to decreased anchorage independent growth and reversed resistance to an EGFR tyrosine kinase inhibitor. Most significantly, orthotopic implantation of XIAP silenced IBC cells revealed the necessity of expression for IBC tumor growth, while overexpression of XIAP enhanced tumor growth. Our findings establish that XIAP augments the malignant properties in IBC by enhancing NFκB function, identify a druggable pathway with multiple targets, and provide feasibility for the development of novel therapeutics targeting the BIR1 domain of XIAP in IBC.
Grant Support: Supported by American Cancer Society, the Duke Cancer Institute as part of the P30 Cancer Center Support Grant NIH CA014236, the Duke Department of Surgery, and DOD grant W81XWH-13-1-0047.
Citation Format: Myron K. Evans, Joseph Geradts, Courtney Edwards, Arianna Price, Arjun J. Arora, Amy J. Aldrich, Adrian Ramirez, Timothy J. Robinson, Peter B. Vermeulen, Steven van Laere, Gayathri R. Devi. XIAP induction by the MAPK-eIF4G1 pathway drives NFκB activation in inflammatory breast cancer growth and therapeutic resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-015.