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/总结 转移通常是癌症死亡的主要原因。尽管所涉及的步骤取得了重大进展 在肿瘤细胞从原发部位转移到远端器官的过程中，我们对分子细节的理解 肿瘤细胞如何进化并获得转移能力尚不清楚。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播散性肿瘤细胞簇为特征 表达基底上皮标志物。其他研究表明癌症干细胞样细胞参与 转移。该提案重点关注叉头盒转录因子 FoxM1，该因子在 侵袭性类型的乳腺癌。该提案基于我们的新发现，令人惊讶的是， FoxM1 与视网膜母细胞瘤 (Rb) 家族蛋白的相互作用对于肿瘤转移很重要。中央 该提案中的假设是，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/促癌基因并抑制分化基因。我们能够 从基因角度剖析抑制功能和激活功能。 Plk1 对 FoxM1 的磷酸化 将 FoxM1 的转录抑制子形式转化为激活子形式。在没有 Plk1-磷酸化的情况下， FoxM1 与 Rb 结合，起到阻遏蛋白的作用。 Plk1 磷酸化-FoxM1 不结合 Rb，而是结合 共激活剂 CBP。与此一致的是，FoxM1 的 Plk1 位点磷酸模拟突变体激活 转录，但无法结合 Rb，也无法抑制分化基因 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。与 FoxM1-/- 不同 小鼠中，除了雌性表现出泌乳不足之外，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 与 FoxM1 +/DD 一样有效，但 FoxM1 DD/DD 小鼠中的肿瘤在转移方面严重缺陷。我们将 使用该小鼠模型和基底样肿瘤模型来研究 FoxM1 的基因抑制功能 驱动转移。目标是： 1. 调查 FoxM1 DD/DD 小鼠的转移缺陷是否与 基底上皮转移细胞和癌症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.研究基底样肿瘤的转移是否需要FoxM1的抑制功能。