Repression function of FoxM1 in metastasis

FoxM1在转移中的抑制功能

• 批准号: 10229508
• 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/10229508
• 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; Prognosis; 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; 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 转移通常是癌症死亡的主要原因。尽管涉及的步骤取得了重大进展 在肿瘤细胞从主要部位到远端器官的转移中，我们对 肿瘤细胞如何发展和获得转移能力是粗略的。在 转移细胞。例如，最近对乳腺癌的研究表征了传播肿瘤细胞的簇 表达基本的上皮标记。其他研究表明癌症干细胞参与 转移。该提案重点介绍了过表达的叉子盒转录因子foxm1 积极的乳腺癌类型。该提案是基于我们的新发现，该发现令人惊讶地表明 FOXM1与视网膜细胞瘤（RB）家族蛋白的相互作用对于肿瘤转移很重要。中央 该提议中的假设是，涉及视网膜母细胞瘤家族的FOXM1的基因抑制函数 蛋白质，在转移性乳腺癌的进展中起关键作用。 FOXM1刺激增殖/亲癌基因并反映分化基因。我们能够 从遗传学上剖析复制函数从激活函数中解剖。 PLK1对FOXM1的磷酸化 将FOXM1的转录复制形式转换为激活剂形式。在没有PLK1磷酸化的情况下， FOXM1与RB结合以充当复制品。 plk1磷酸化 - 福克米1不结合rb，而是结合 共激活器CBP。与此相一致，FOXM1的PLK1点磷酸模拟突变体激活 转录，但未能结合Rb，无法抑制分化基因GATA3。我们已经产生了 表达FOXM1（FOXM1DD）表达缺陷突变体的敲入小鼠应变。与FoxM1不同 - / - 小鼠，没有明显的发育缺陷，除了女性在泌乳中表现出缺陷。 有趣的是，FOXM1DD/DD小鼠支持MMTV-PYMT驱动的乳腺肿瘤的发育 有效地像FOXM1 +/DD一样有效，但是FOXM1 DD/DD小鼠中的肿瘤严重缺乏转移。我们将 使用此小鼠模型和基本肿瘤模型来研究FOXM1的基因表达功能 驱动转移。目的是： 1。研究FOXM1 DD/DD小鼠中的转移缺乏是否与缺陷有关 基本上皮转移细胞和癌干细胞的发展。 2。研究FOXM1再现了调节转移细胞进化的基因。 3。研究FOXM1的表达功能是否需要基本样肿瘤的转移。