Repression function of FoxM1 in metastasis

FoxM1在转移中的抑制功能

• 批准号: 9910845
• 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
• 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/9910845
• 关键词: BRCA1 gene; Binding; Biological Markers; Breast cancer metastasis; Carcinoma; Cells; Characteristics; Chromatin; Cytokeratin; Defect; Development; Differentiated Gene; Distal; Epithelial; Epithelial Cells; 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/Corepressor; 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

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.

摘要/摘要 转移往往是癌症致死的主要原因。尽管在所涉及的步骤上取得了重大进展 在肿瘤细胞从原发部位转移到远端器官的过程中，我们对 肿瘤细胞是如何进化并获得转移能力的，目前尚不清楚。在这方面已经取得了一些进展 转移细胞。例如，最近对乳腺癌的研究以扩散的肿瘤细胞群为特征。 表达基底上皮标志物。其他研究表明，癌症干细胞参与了 转移。这项建议关注的是叉头盒转录因子FOXM1，该因子在 侵袭性类型的乳腺癌。这项建议是基于我们的新发现，这些发现令人惊讶地表明 FOXM1的S与视网膜母细胞瘤(Rb)家族蛋白的相互作用在肿瘤转移中起重要作用。中环 这个建议中的假设是，FOXM1的基因抑制功能，涉及视网膜母细胞瘤家族 蛋白质在转移性乳腺癌的进展中起着关键作用。 FOXM1刺激增殖/致癌基因，抑制分化基因。我们能够 从基因上将阻遏功能与激活功能分开。Plk1对FOXM1的磷酸化作用 将转录抑制子形式的FOXM1转换为激活形式。在没有Plk1-磷酸化的情况下， FOXM1与Rb结合，发挥抑制因子的作用。PLK1磷酸化-FOXM1不结合RB，而是结合到 共同激活者CBP。与此一致的是，FOXM1的Plk1位点磷酸模拟突变体激活 转录，但不能结合RB，也不能抑制分化基因GATA3。我们已经生成了一个 表达FOXM1(FoxM1DD)抑制缺陷突变体的敲入小鼠品系。不像FOXM1-/- 除了雌性小鼠表现出哺乳缺陷外，没有明显的发育缺陷。 有趣的是，FoxM1DD/DD小鼠支持MMTV-PyMT驱动的乳腺肿瘤的发展，如 有效率为FOXM1+/DD，但FOXM1/DD小鼠肿瘤转移严重不足。我们会 使用该小鼠模型和基底细胞样瘤模型来研究FOXM1的基因抑制功能 会导致肿瘤转移。目标是： 1.研究FOXM1DD/DD小鼠转移缺陷是否与肿瘤转移缺陷有关 基底上皮转移细胞和肿瘤干细胞样细胞的发育。 2.研究调控转移细胞进化的FOXM1抑制基因。 3.探讨基底样肿瘤的转移是否需要FOXM1的抑制功能。