Abstract LB-123: STAT3 mediates APC-driven chemoresistance in breast cancer

Abstract

Abstract Breast tumors frequently develop resistance to treatment with a variety of standard (i.e. cisplatin or doxorubicin) or targeted chemotherapeutic agents, resulting in tumor recurrence and increased patient mortality. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost by hypermethylation or mutation in up to 70% of sporadic breast cancers; however, the downstream effects of APC loss have not been well explored in breast cancer. Heterozygous Apc mutation using the ApcMin/+ mouse model enhanced tumorigenesis in the mouse mammary tumor virus - Polyoma Middle T transgenic model (MMTV-PyMT). Cells isolated from MMTV-PyMT;ApcMin/+ mice are resistant to chemotherapy, express higher levels of multidrug resistance protein 1 (MDR1), and have a greater population of tumor initiating cells (TICs) compared to controls. Here we demonstrate that APC loss-of-function cells have increased activation of signal transducer and activator of transcription 3 (STAT3) and the anti-apoptotic protein Mcl-1. STAT3 over-expression is common in breast cancer, leads to poor prognosis, and up-regulates MDR1 expression leading to chemotherapeutic resistance. To explore the functional role of STAT3 in mediating therapeutic resistance in APC loss-of-function models, we examined the impact of STAT3 inhibition on MDR1 and the TIC population to cause therapeutic resistance in the MMTV-PyMT;ApcMin/+ vs MMTV-PyMT;Apc+/+ murine breast cancer cells. We have made the novel observation that chemotherapy treatment has a time-dependent effect on the activation of STAT3 and expression of Mcl-1 specific to Apc-mutant cells. Finally, we have assessed the use of STAT3 inhibitors in combination with standard chemotherapy to alleviate APC-mediated resistance. Combined these data suggest that loss of APC activates STAT3-driven pathways resulting in the development of chemotherapeutic resistance. Citation Format: Monica K. VanKlompenberg, Emily A. Leyden, Jian-Ting Zhang, Jenifer R. Prosperi. STAT3 mediates APC-driven chemoresistance in breast cancer. [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-123.