Role of IFN inducible transmembrane protein 1 in AI-resistant breast cancer

IFN诱导跨膜蛋白1在AI耐药乳腺癌中的作用

• 批准号: 9051028
• 负责人: Asona Lui
• 金额: $ 2.98万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9051028
• 关键词: Address; Aggressive behavior; Alternative Therapies; Aromatase; Aromatase Inhibitors; Attention; Basement membrane; Binding; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Cancer Prognosis; Cell Death; Cell Line; Cell Survival; Cell model; Cells; Cessation of life; Complex; Development; Enzymes; Estrogen Receptors; Estrogens; Exhibits; Family; Foundations; Future; Generations; Genes; Goals; Growth; Hormones; IFNAR1 gene; Immune system; Immunohistochemistry; In Vitro; Integral Membrane Protein; Interferon Receptor; Interferon Type I; Interferon-alpha; Interferons; Invaded; Lentivirus Vector; Life; Luciferases; MCF7 cell; Mammary Duct; Mammary Neoplasms; Mediating; Methods; Modeling; Mus; Pathway interactions; Patients; Phenotype; Phosphorylation; Physicians; Play; Primary Neoplasm; Production; Proteins; Public Health; Reporter; Reporting; Resistance; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; STAT protein; STAT1 gene; Scientist; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Staining method; Stains; Therapeutic; Viral; Virus Diseases; Western Blotting; Woman; anticancer research; chromatin immunoprecipitation; chromatin remodeling; cytokine; deprivation; expression vector; in vivo; inhibitor/antagonist; insight; loss of function; mRNA Expression; malignant breast neoplasm; novel; oncology; overexpression; prevent; promoter; protein expression; public health relevance; receptor; targeted treatment; therapy development; therapy resistant; transcription factor; tumor; tumor growth; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant) 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 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). We have found that IFITM1 is overexpressed in both this AI-resistant cell model and AI-resistant breast tumors isolated from patients. IFITM1 is not normally expressed by cells and is only produced following stimulation with interferons (IFNs). Mechanistic studies have revealed that elevated IFNα drives IFITM1 expression through the IFNα receptor (IFNAR). Most notably, loss of IFITM1 expression induces the death of the AI-resistant MCF-7:5C cells, suggesting that inhibiting this pathway might hold therapeutic promise. We hypothesize that JAK/STAT signaling from IFNAR utilizes specific interferon sensitive response elements (ISRE) in the IFITM1 promoter to drive expression and that IFITM1 overexpression allows the AI-resistant MCF-7:5C cells to maintain their aggressive phenotype in vivo. In order to address this hypothesis we propose the following specific aims: Aim 1: Identify the mechanism by which JAK/STAT signaling stimulates IFITM1 overexpression in AI-resistant breast cancer cells. Aim 2: Determine whether IFITM1 overexpression provides a functional advantage to AI-resistant cells in vivo. In aim 1 we will utilize chromatin immunoprecipitation (CHIP) assays and luciferase reporters to determine which transcription factors drive IFITM1 overexpression and to investigate the motifs utilized in the IFITM1 promoter. In aim 2, we will utilize inducible lentivirial expression vectors to produce gain and loss of function clones of our cell lines. The impact of altered IFITM1 expression on the invasive and tumorigenic potential of AI-sensitive and AI- resistant breast cancer cells will be determined using the mouse intraductal (MIND) model of invasive breast cancer progression. The insights gained from this study will further our understanding of the role that IFN signaling and IFN stimulated genes play in breast cancer prognosis and resistance to therapy. The proposed project will also provide a foundation for my future as a Physician Scientist in the field of Oncology.