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Mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions

FIP200通过自噬和非自噬功能调控乳腺癌的机制

基本信息

批准号：
9381905
负责人：
JUN-LIN GUAN
金额：
$ 36.46万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381905
关键词：
Ablation Acute Alleles Animal Model Apoptosis Autophagocytosis BRCA1 gene Binding Biological Process Breast Cancer Cell Breast Cancer Model Breast Epithelial Cells Breast cancer metastasis Cancer Relapse Cell physiology Cells Characteristics Complement Complex DNA Sequence Alteration Data Development Disease Embryo Epidermal Growth Factor Receptor Family Goals Growth Health Homeostasis Human Impairment Incidence Knock-in Knock-in Mouse Knowledge Laboratories Maintenance Malignant Neoplasms Mammary Neoplasms Mediating Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Neoplasm Metastasis PTK2 gene Patients Play Population Property Proteins Recurrent disease Regulation Relapse Role Signal Transduction Starvation Stat3 Signaling Pathway System TNF gene Transforming Growth Factor Beta 2 Transforming Growth Factor beta Tumorigenicity Woman aldehyde dehydrogenases antitumor effect base cancer therapy conditional mutant genetic analysis genetic approach immune function in vivo insight malignant breast neoplasm mouse model mutant neoplastic cell novel novel therapeutics response stem-like cell targeted treatment tool transforming growth factor beta3 tumor tumor growth tumor progression tumorigenic

项目摘要

Breast cancer is the most common malignancy among US women and remains a major health threat with high incidence and lethality. Despite the remarkable progress made recently in deciphering the genetic mutations associated with breast cancer, our understanding of the mechanistic basis for metastasis and relapse of breast cancer is still very limited. The long-term goal of the proposed studies is to understand the molecular and cellular mechanisms involved in these properties of breast cancer cells that are ultimately responsible for patient lethality. FIP200 (FAK-family Interacting Protein of 200 kDa) was initially identified in our laboratory and subsequently shown to be a component of the ULK1/Atg13/FIP200 complex essential for the induction of autophagy. We have shown recently that FIP200 ablation inhibited the development and progression of breast cancer, providing the first evidence of a pro-tumorigenic role for autophagy in animal models with intact immune functions. We also developed an inducible system to delete FIP200 after tumor development in vivo and demonstrated that acute disruption of autophagy by FIP200 deletion in established tumors blocked their growth. In preliminary studies, we identified two distinct populations of breast cancer stem-like cells (BCSCs) and showed that FIP200 ablation impaired the maintenance and tumorigenicity of both BCSCs. Our preliminary data implicated TGF-β/Smad and EGFR/Stat3 signaling pathways in mediating FIP200 regulation of these two BCSCs respectively. In another set of preliminary studies, we identified residues 582-585 in FIP200 for binding to Atg13 and generated a new FIP200 knock-in mutant mouse with these residues mutated to Ala (designated as KI allele, encoding FIP200-4A lacking binding to Atg13). Analysis of KI/KI mice and MEFs derived from KI/KI embryos showed both autophagy and non-autophagy functions of FIP200 in regulating different biological processes. These studies further revealed a new non-autophagy function of FIP200 to protect normal and transformed MEFs from TNFα-induced apoptosis. Thus this unique mutant KI allele as well as additional mouse models prepared in preliminary studies provides us with powerful tools for the genetic analysis of mechanisms of FIP200 regulation of breast cancer through its autophagy and non-autophagy functions in vivo. Based on these strong preliminary data and using our unique novel mouse models, we propose to 1) determine the mechanisms of FIP200 regulation of CD29hiCD61+ and ALDH+ BCSCs in PyMT and BRCA1-deficient mouse models of breast cancer; 2) examine autophagy and non-autophagy functions of FIP200 in the regulation of BCSCs and breast cancer development and progression; and 3) explore the strategies of targeting FIP200 autophagy and non-autophagy functions in BCSCs for breast cancer therapy. Together, these studies will provide significant insights into the molecular and cellular mechanisms of breast cancer metastasis and relapse that may contribute to novel therapies for this devastating disease.

乳腺癌是美国女性中最常见的恶性肿瘤，仍然是女性的主要健康威胁