Abstract 4888: Disrupting MUC1/IFITM1 crosstalk reverses the aggressive phenotype of aromatase inhibitor-resistant breast cancer

Abstract

Abstract Breast cancer is the most commonly diagnosed and second most lethal cancer among women, affecting over 252,000 women in 2017. The ER+/PR+ subtype of breast cancer is the most frequently diagnosed, representing approximately 70% of all cases. Estrogen depletion through aromatase inhibitors (AIs) is the standard of care to cause tumor regression in the ER+ subtype. Our research focuses on targeting the AI-resistant tumors that develop in 30% of women. The human oncoprotein, mucin 1 (MUC1), drives tumorigenesis in breast carcinomas promoting the epithelial-mesenchymal transition, epigenetic reprogramming, and evasion of the immune response. MUC1 interacts with the STAT proteins, via the JAK/STAT signaling pathway, and stimulates transcription of interferon-stimulated genes (ISGs) including IFITM1. Our laboratory has shown that IFITM1 is overexpressed in AI-resistant breast cancer cells and AI-resistant tumors and promotes an aggressive phenotype. In this study, we demonstrate that MUC1 is differentially regulated in endocrine-sensitive (MCF-7 and T-47D) compared to AI-resistant (MCF-7:5C) cells and that it plays a critical role in enhancing IFITM1 expression in the resistant cells. Analysis of a tumor microarray of 94 ER+ human breast tumors indicated that co-expression of both MUC1 and IFITM1 correlated with poor recurrence-free survival, poor overall survival, and AI resistance. To investigate how disruption of the MUC1/IFITM1 crosstalk effects cell survival and proliferation, we used an AI-resistant cell line (MCF-7:5C) that overexpresses MUC1, P-STAT1, and IFITM1. We genetically manipulated breast cancer cells by knocking down the levels of MUC1 with siRNA and observed lowered expression of IFITM1 at the mRNA and protein level and reduced IFITM1 promoter activation. Additionally, knockdown of MUC1 and IFITM1 levels with siRNA induced cell death in AI-resistant cells (MCF-7:5C). We verified this effect with the pharmacologic inhibitors GO-201 (a MUC1 inhibitor) and ruxolitinib (a JAK/STAT inhibitor) to interfere with the MUC1/IFITM1 crosstalk in vitro. Both agents significantly reduced cell proliferation in resistant cells (MCF-7:5C) but not in estrogen-sensitive cell lines (MCF-7 and T-47D). Co-IP confirmed the physical interaction between MUC1 and STAT1/2 and ruxolitinib treatment blocked this interaction by inhibiting STAT phosphorylation in both AI-resistant and -sensitive cells. In vivo studies using ruxolitinib significantly reduced tumor size in NSG mice and decreased expression of MUC1, P-STAT1, and IFITM1. The research discussed here highlights a novel mechanism by which breast cancer cells develop AI resistance and suggests that disrupting MUC1/IFITM1 crosstalk might be therapeutically beneficial to patients with AI-resistant disease. Citation Format: Taylor E. Escher, Eric Geanes, Asona Lui, Joan Lewis-Wambi. Disrupting MUC1/IFITM1 crosstalk reverses the aggressive phenotype of aromatase inhibitor-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4888.