Repression function of FoxM1 in metastasis

FoxM1在转移中的抑制功能

• 批准号: 10670759
• 负责人: Pradip Raychaudhuri
• 金额: $ 35.85万
• 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/10670759
• 关键词: BRCA1 gene; Binding; Biological Markers; Breast cancer metastasis; Carcinoma; Cells; Characteristics; Chromatin; Cytokeratin; Defect; Development; Differentiated Gene; Distal; Epithelial Cells; Epithelium; Evolution; Exhibits; FOXM1 gene; Female; G1 Phase; GATA3 gene; Genes; Genetic Transcription; 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; Proliferating; Protein Family; Proteins; Recurrent Malignant Neoplasm; Repression; Retinoblastoma; Role; Site; TP53 gene; Testing; Transcription Repressor; cancer recurrence; design; effective therapy; gene repression; malignant breast neoplasm; mimetics; mouse model; mutant; neoplastic cell; novel; overexpression; polyoma middle tumor antigen; 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/概要 转移通常是癌症致死的主要原因。尽管在所涉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还不清楚。已经取得了一些进展， 转移细胞例如，最近的研究表明，乳腺癌的特点是肿瘤细胞的扩散 表达基底上皮标记物。其他研究表明，癌症干细胞样细胞参与了 转移这项提议集中在叉头盒转录因子FoxM 1上，FoxM 1在细胞中过度表达， 侵袭性乳腺癌这项提议是基于我们的新发现，令人惊讶的是， FoxM 1与视网膜母细胞瘤（Rb）家族蛋白的相互作用对于肿瘤转移是重要的。中央 该建议中的假设是，FoxM 1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。 FoxM 1刺激增殖/促癌基因并抑制分化基因。我们能够 从遗传学上将阻遏物功能与激活功能分开。Plk 1对FoxM 1的磷酸化作用 将FoxM 1的转录阻遏物形式转化为激活物形式。在没有Plk 1磷酸化的情况下， FoxM 1与Rb结合作为阻遏物发挥作用。Plk 1磷酸化-FoxM 1不结合Rb，而是结合 辅助激活剂CBP。与此一致，FoxM 1的Plk 1位点磷酸模拟突变体激活了 转录，但不能结合Rb和不能抑制分化基因GATA 3。我们创造了一个 表达FoxM 1阻遏缺陷突变体（FoxM 1DD）的敲入小鼠品系。与FoxM 1-/-不同 小鼠没有明显的发育缺陷，除了雌性小鼠表现出泌乳不足。 有趣的是，FoxM 1DD/DD小鼠支持MMTV-PyMT驱动的乳腺肿瘤的发展， FoxM 1 +/DD小鼠中的肿瘤与FoxM 1 +/DD小鼠中的肿瘤一样有效，但FoxM 1 DD/DD小鼠中的肿瘤在转移方面严重缺陷。我们将 我用这个小鼠模型和基底细胞样肿瘤模型来研究FoxM 1的基因抑制功能 导致转移。其目标是： 1.研究FoxM 1 DD/DD小鼠中的转移缺陷是否与FoxM 1基因缺陷有关。 基底上皮转移细胞和癌干细胞样细胞的发展。 2.研究调节转移细胞进化的FoxM 1抑制基因。 3.研究FoxM 1的抑制功能是否是基底细胞样肿瘤转移所必需的。