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Repression function of FoxM1 in metastasis

FoxM1在转移中的抑制功能

基本信息

批准号：
10020378
负责人：
Pradip Raychaudhuri
金额：
$ 36.58万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10020378
关键词：
BRCA1 gene Binding Biological Markers Breast cancer metastasis Carcinoma Cells Characteristics Chromatin Cytokeratin Defect Development Differentiated Gene Distal Epithelial Epithelial Cells Epithelium Evolution Exhibits FOXM1 gene Female G1 Phase GATA3 gene Genes Genetic Transcription Head Impairment Knock-in Mouse Lactation Malignant Neoplasms Mammary Neoplasms Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Mouse Mammary Tumor Virus Mouse Strains Mus Neoplasm Metastasis Oncogenes Organ P-Cadherin Phosphorylation Play Population Protein Family Proteins Repression Retinoblastoma Role Site TP53 gene Testing Transcription Repressor base cancer recurrence design effective therapy gene repression malignant breast neoplasm mimetics mouse model mutant neoplastic cell novel outcome forecast overexpression public health relevance stem-like cell transcription factor tumor

项目摘要

Abstract/Summary Metastasis is often the main cause of fatality from cancer. Despite significant progresses on the steps involved in metastasis of tumor cells from a primary site to distal organs, our understanding of the molecular details of how tumor cells evolve and acquire the ability to metastasize is sketchy. Some progress has been made on the metastatic cells. For example, recent studies in breast cancer characterized cluster of disseminating tumor cells expressing basal epithelial markers. Other studies indicated involvement of the cancer stem-like cells in metastasis. This proposal focuses on the fork-head box transcription factor FoxM1 that is over-expressed in aggressive types of breast cancer. The proposal is based on our new findings, which surprisingly indicate that FoxM1’s interaction with the retinoblastoma (Rb) family proteins is important for tumor metastasis. The central hypothesis in this proposal is that, the gene-repression function of FoxM1, involving the retinoblastoma family proteins, plays critical roles in the progression of metastatic breast cancer. FoxM1 stimulates proliferation/pro-cancer genes and represses differentiation genes. We were able to genetically dissect the repressor function from the activation function. Phosphorylation of FoxM1 by Plk1 converts a transcriptional repressor form of FoxM1 to an activator form. In the absence of Plk1-phosphorylation, FoxM1 binds to Rb to function as a repressor. Plk1 phosphorylated-FoxM1 does not bind Rb, instead it binds to the co-activator CBP. Consistent with that, a Plk1-sites phospho-mimetic mutant of FoxM1 activates transcription, but fails to bind Rb and fails to repress the differentiation gene GATA3. We have generated a knock-in mouse strain that expresses the repression-deficient mutant of FoxM1 (FoxM1DD). Unlike FoxM1-/- mice, there is no overt developmental defect, except that the females exhibit deficiencies in lactation. Interestingly, the FoxM1DD/DD mice support MMTV-PyMT-driven development of mammary tumors as efficiently as FoxM1 +/DD, but the tumors in FoxM1 DD/DD mice are severely deficient in metastasis. We will use this mouse model and a model for basal-like tumors to investigate how gene repression function of FoxM1 drives metastasis. The aims are: 1. Investigate whether metastasis deficiency in the FoxM1 DD/DD mice is related to deficiencies in the development of the basal epithelial metastatic cells and cancer stem-like cells. 2. Investigate the FoxM1 repressed genes that regulate evolution of metastatic cells. 3. Investigate whether the repression function of FoxM1 is required for metastasis of basal-like tumors.

抽象/总结