Journal
MOLECULAR CANCER RESEARCH
Volume 17, Issue 5, Pages 1180-1194Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-18-0916
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Funding
- NIH/NIGMS COBRE grant [P20GM104936, P30 GM10332]
- KU Cancer Center's Support Grant [P30 CA168524]
- Department of Defense [W81XWH-12-1-0139]
- National Cancer Institute [K01CA120051, 1F30CA203160-01]
- University of Kansas Medical Center (KUMC)
- KUMC Biomedical Research Training Program (BRTP)
- American Medical Association (AMA) Foundation
- University of Kansas Cancer Center (CCSG) [P30 CA168524-0]
- University of New Mexico Comprehensive Cancer Center (GMaP grant) [3P30CA118100-12S2]
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The human oncoprotein, mucin 1 (MUC1), drives tumorigenesis in breast carcinomas by promoting epithelial-to-mesenchymal transition (EMT), epigenetic reprogramming, and evasion of immune response. MUC1 interacts with STAT1, through JAK/STAT signaling, and stimulates transcription of IFN-stimulated genes, specifically IFN-induced transmembrane protein 1 (IFITM1). Our laboratory has previously shown that IFITM1 overexpression in aromatase inhibitor (AI)-resistant breast cancer cells promotes aggressiveness. Here, we demonstrate that differential regulation of MUC1 in AI-sensitive (MCF-7 and T-47D) compared with AI-resistant (MCF-7:5C) cells is critical in mediating IFITM1 expression. A tumor microarray of 94 estrogen receptor-positive human breast tumors correlated coexpression of MUC1 and IFITM1 with poor recurrence-free survival, poor overall survival, and AI-resistance. In this study, we investigated the effects of MUC1/IFITM1 on cell survival and proliferation. We knocked down MUC1 levels with siRNA and pharmacologic inhibitors, which abrogated IFITM1 mRNA and protein expression and induced cell death in AI-resistant cells. In vivo, estrogen and ruxolitinib significantly reduced tumor size and decreased expression of MUC1, P-STAT1, and IFITM1.
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