Abstract
Abstract Breast cancer can be separated into estrogen receptor/ progesterone receptor positive (ER+/PR+), Her2/neu positive (HER2+), and triple negative (ER-/PR-/HER2-) subtypes. Additionally, breast cancer may manifest clinically as either non-inflammatory or inflammatory disease. Inflammatory breast cancer is a highly lethal subtype of breast carcinoma that may express any of the three aforementioned receptors. Our laboratory has found that a novel marker, interferon-induced transmembrane protein 1 (IFITM1), is overexpressed in multiple subtypes of breast cancer and its overexpression is associated with poor overall survival as well as resistance to endocrine therapy, chemotherapy, and radiation. IFITM1 is a type 1 interferon (IFN) stimulated gene that is not expressed in normal breast tissue, and is only induced upon IFN exposure. In this study, we conducted immunohistochemical staining for IFITM1 in 94 ER+ human breast tumor samples and discovered that high IFITM1 expression was associated with increased clinical stage and resistance to endocrine therapy. Elevated expression of IFITM1 was also detected in human triple negative breast cancer (TNBC) samples as compared to normal breast tissue. Notably, this overexpression was most pronounced in TNBC tumors from African American (AA) patients. We screened a panel of nine cell lines that represent all major subtypes of breast cancer and found IFITM1 overexpression in ER+ aromatase inhibitor-resistant MCF-7:5C, AA-derived triple negative MDA-MB-468 and MDA-MB-157, and triple negative inflammatory SUM149 cells. We used inducible shRNA and CRSPR/Cas9 respectively, to investigate the effect of IFITM1 knockdown on MCF-7:5C and SUM149 xenograft tumors using two in vivo breast cancer models. The orthotopic (mammary fat pad) model evaluated tumor proliferation, and the mammary intraductal (MIND) model assessed tumor cell invasion out of the milk duct. We found that loss of IFITM1 in MCF-7:5C and SUM149 cells significantly inhibited their ability to form tumors in vivo and it completely blocked their ability to invade out of the milk duct. Additional studies indicated that hyper-activated JAK/STAT signaling was responsible for driving IFITM1 expression in MCF-7:5C, MDA-MB-468, and SUM149 cells. Furthermore, we demonstrated that JAK/STAT activation can be targeted in vivo with the FDA approved JAK inhibitor ruxolitinib (Jakafi™). Oral treatment of mice with 50 μg/g bodyweight ruxolitinib reduced IFITM1 expression and inhibited the growth of both MCF-7:5C and MDA-MB-468 tumors by loss of STAT1/2 phosphorylation. The overexpression of IFITM1 in three distinct breast cancer subtypes indicates that IFITM1 may be a targetable marker of aggressive disease in general and may open the door for novel therapies of treatment-refractory breast cancer. Citation Format: Asona Lui, Joshua Ogony, Jordan Marquess, Eric Geanes, William Jewell, Ikbale El Ayachi, Gustav Miranda-Carboni, Ossama Tawfik, Joan Lewis-Wambi. The clinical relevance of targeting IFITM1 in three distinct subtypes of aggressive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3848. doi:10.1158/1538-7445.AM2017-3848
Published Version
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