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dc.contributor.advisorLewis-Wambi, Joan
dc.contributor.advisorGeiger, Paige
dc.contributor.authorLui, Asona Lui
dc.date.accessioned2018-02-01T04:06:36Z
dc.date.available2018-02-01T04:06:36Z
dc.date.issued2017-05-31
dc.date.submitted2017
dc.identifier.otherhttp://dissertations.umi.com/ku:15348
dc.identifier.urihttp://hdl.handle.net/1808/25887
dc.description.abstractBreast cancer remains the leading malignancy among women in the United States, affecting an estimated 246,660 women in 2016. Breast cancer can be separated into three groups known as estrogen receptor/ progesterone receptor positive (ER+/PR+), Her2/neu positive (HER2+), and triple negative (ER-/PR-/HER2-) subtypes. The majority of breast cancers rely on estrogen to stimulate their growth and survival. Estrogen is produced from precursor hormones by the aromatase enzyme, whose action can be blocked with aromatase inhibitors (AIs). Unfortunately ~40% of breast cancer patients are resistant to this treatment and their breast tumors either continue to grow or recur despite depletion of circulating estrogen. The precise cause of AI-resistance is not known. Our lab aims to determine the mechanisms that allow breast cancer cells to survive in estrogen-depleted conditions. We have previously reported the generation of an AI-resistant breast cancer cell line, MCF-7:5C, which was isolated under estrogen-free conditions from the estrogen-dependent breast cancer cell line MCF-7. The MCF-7:5C cell line is highly aggressive and overexpresses several interferon stimulated genes including, interferon inducible transmembrane protein 1 (IFITM1). IFITM1 is a type 1 interferon (IFN) stimulated gene (ISG) that is not expressed in normal breast tissue, and is only induced by the type1 IFNs (IFNα and β) to protect the host from viral infections. IFNα signals through a specific receptor, IFNAR, which uses JAK/STAT signaling to produce the ISGs. ISGs are known to drive the progression of other cancer types, to inhibit apoptosis and promote DNA damage resistance. However, the significance of constitutive overexpression of ISGs in AI-resistant breast cancer is not known. We hypothesize that IFITM1 overexpression contributes the AI-resistant phenotype and promotes breast cancer cell aggression and survival. In this thesis, we demonstrate that IFITM1 is overexpressed in breast tumors and is correlated with poor response to endocrine therapy using in silico analysis of breast tumor expression databases and a human tissue microarray. Gain and loss of function studies in an IFITM1-overexpressing AI-resistant breast cancer cell line, MCF-7:5C, and an IFITM1-null AI-sensitive breast cancer cell line, MCF-7, reveal that IFITM1 promotes the AI-resistant aggressive phenotype and estrogen-independent growth. Additionally, the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer evaluate the role of IFITM1 in tumor growth and invasion respectively. We report that loss of IFITM1 induced cell death in AI-resistant MCF-7:5C cells results in marked increases in p21/Waf1/Cip1 transcription, expression and nuclear localization. Notably, p21 transcriptional upregulation was mediated by STAT1 activation. These findings suggest IFITM1 overexpression contributes directly to breast cancer progression and that it may be a therapeutically relevant target in the treatment of endocrine-resistant breast cancer. Mechanistic studies reveal that MCF-7:5C cells produce elevated levels of IFN as compared to MCF-7 cells and that this cytokine binds to the type 1 IFN receptor, IFNAR, and induces JAK/STAT signaling, ultimately resulting in the overexpression of IFITM1. Independently, we also find that mucin 1 (MUC1) associates with STAT1 and stabilizes its phosphorylated form, thereby contributing directly to IFITM1 expression. MUC1 expression is hormonally controlled and is normally enhanced by estrogen stimulation. We find that MUC1 expression is dysregulated in AI-resistant MCF-7:5C cells and is instead reduced by estrogen stimulation. MCF-7:5C cells are sensitive to apoptosis following exposure to estrogen, which can be enhanced by loss of IFITM1 expression. Loss of MUC1 expression similarly enhances estrogen-induced apoptosis, suggesting that the communication between MUC1 and STAT1 also influences estrogen signaling in AI-resistant breast cancer. In this thesis, we conduct investigations into the mechanisms and functional significance of IFITM1 expression in AI-resistant breast cancer and conclude that IFITM1 overexpression may be a targetable marker of AI-resistant disease.
dc.format.extent197 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectCellular biology
dc.subjectOncology
dc.subjectPathology
dc.subjectAromatase inhibitor resistance
dc.subjectBreast cancer
dc.subjectEndocrine resistance
dc.subjectIFITM1
dc.subjectInterferon signaling
dc.subjectMammary intraductal model
dc.titleThe role of IFITM1 in promoting breast cancer aggression and aromatase-inhibitor resistance
dc.typeDissertation
dc.contributor.cmtememberAnant, Shrikant
dc.contributor.cmtememberBehbod, Fariba
dc.contributor.cmtememberDixon, Dan
dc.contributor.cmtememberDhar, Animesh
dc.contributor.cmtememberFields, Timothy
dc.thesis.degreeDisciplineMolecular & Integrative Physiology
dc.thesis.degreeLevelPh.D.
dc.identifier.orcid
dc.identifier.orcidhttps://orcid.org/0000-0002-0076-3492
dc.rights.accessrightsopenAccess


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