FoxM1 in breast cancer.

FoxM1 在乳腺癌中的作用。

• 批准号: 9251769
• 负责人: Pradip Raychaudhuri
• 金额: $ 32.54万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-13 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251769
• 关键词: Age; Antineoplastic Agents; Biological Markers; Breast Cancer Cell; Cancer Etiology; Cell Culture Techniques; Cell Differentiation process; Cells; Cessation of life; Clinic; CpG Islands; Development; Diagnosis; Disease; ERBB2 gene; Embryo; Exhibits; FOXM1 gene; Frequencies; Gene Expression Profile; Genetic Transcription; Goals; Hypermethylation; Maintenance; Mammary Neoplasms; Mammary gland; Modeling; Molecular; Mouse Mammary Tumor Virus; Mutation; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Population; Protein Family; Recruitment Activity; Recurrent disease; Relapse; Repression; Role; Specimen; Testing; Therapeutic; Transcription Coactivator; Transcriptional Activation; Tumor Suppressor Proteins; Undifferentiated; Woman; base; cell type; insight; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; outcome forecast; overexpression; progenitor; promoter; public health relevance; stem; tumor; tumor progression

DESCRIPTION (provided by applicant): Breast cancer is a leading cause of cancer-related deaths in women of all ages. Despite advances on diagnosis and therapy, the rate of mortality remains high. While it is a heterogeneous disease associated with diverse genetic changes, the aggressiveness of breast cancers strongly correlates with the level of differentiation. For example, the high-grade tumors contain poorly differentiated cells and exhibit ES (embryonic stem) like gene expression signature. These tumors relapse with high frequency, they are metastatic and they respond poorly to the available therapies. The goal of this proposal is to investigate the mechanism that leads to high-grade progression. We will test the hypotheses that the transcriptional regulator FOXM1 plays a major causal role in the development of high-grade, aggressive breast cancer, and that inhibition of FOXM1 will impede high-grade progression by inducing tumor differentiation. The hypotheses are based on the following observations, First, FOXM1 is over-expressed in HER2- amplified, ER-, and in the triple negative (ER-, PR- and HER2-) basal-like types of breast cancers. Moreover, there is a strong correlation between poorly differentiated breast cancers and over-expression of FOXM1. In normal mammary gland, over-expression of FOXM1 increases the population of luminal progenitors, while deletion of FoxM1 depletes the progenitor/stem pool and increases the differentiated luminal cells. FOXM1 increases the progenitor pool by inhibiting expression of GATA-3, a master activator of luminal differentiation. Interestingly, FOXM1 inhibits expression of GATA-3 by inducing hypermethylation of the CpG islands in its promoter through recruitment of DNMT3B. Surprisingly, the inhibition of GATA-3 by FOXM1 involves the RB tumor suppressor protein. These observations on luminal differentiation suggest the possibility that FOXM1 plays a direct role in the high-grade progression. Our mechanistic model is that FOXM1 drives accumulation of the poorly differentiated breast cancer cells by repressing GATA-3 and other luminal factors. We will use both cell culture and mouse models to investigate these new functions of FOXM1. Also, we plan to investigate the roles of RB because many drugs, directly or indirectly, cause activation of RB, which, in case of the FOXM1 overexpressing tumors, would support accumulation of the poorly differentiated cells through inhibition of GATA-3. Further, we will investigate the hypothesis that targeting FOXM1 will induce differentiation in high- grade tumors. The aims are: 1. Investigate the roles of FOXM1 overexpression in the accumulation of poorly differentiated breast cancer cells. 2. Investigate how phosphorylation impacts FOXM1's ability to regulate mammary/tumor differentiation. 3. Investigate the role of the FOXM1/RB interaction in the accumulation of poorly differentiated breast cancer cells. Overall, the studies will have significant impact towards an understanding of the molecular mechanism underlying high-grade progression of breast cancers. The notion that over-expressed FOXM1 recruits RB to induce accumulation of poorly differentiated tumor cells is expected to have significant impact in the clinic because many anti-cancer drugs generate active RB, which in FOXM1 over-expressing tumors would generate cells that cause relapse of the disease in an aggressive form.

描述（由申请人提供）：乳腺癌是所有年龄段女性癌症相关死亡的主要原因。尽管在诊断和治疗方面取得了进展，但死亡率仍然很高。虽然它是一种与多种遗传变化相关的异质性疾病，但乳腺癌的侵袭性与分化水平密切相关。例如，高级别肿瘤含有低分化细胞，并表现出ES（胚胎干）样基因表达特征。这些肿瘤复发的频率很高，它们是转移性的，对现有的治疗反应很差。本提案的目的是研究导致高等级进展的机制。我们将验证以下假设：转录调节因子FOXM1在高级别侵袭性乳腺癌的发展中起主要的因果作用，FOXM1的抑制将通过诱导肿瘤分化来阻碍高级别进展。这些假设基于以下观察：首先，FOXM1在HER2扩增型、ER-型和三阴性（ER-、PR-和HER2-）基底样乳腺癌中过表达。此外，低分化乳腺癌与FOXM1的过表达有很强的相关性。在正常乳腺中，FOXM1的过表达增加了腔内祖细胞的数量，而FOXM1的缺失则耗尽了祖/干池，增加了分化的腔内细胞。FOXM1通过抑制GATA-3的表达来增加祖细胞库，GATA-3是管腔分化的主要激活因子。有趣的是，FOXM1通过募集DNMT3B来诱导启动子CpG岛的超甲基化，从而抑制GATA-3的表达。令人惊讶的是，FOXM1对GATA-3的抑制涉及RB肿瘤抑制蛋白。这些关于管腔分化的观察结果表明FOXM1可能在高级别进展中起直接作用。我们的机制模型是FOXM1通过抑制GATA-3和其他腔因子来驱动低分化乳腺癌细胞的积累。我们将使用细胞培养和小鼠模型来研究FOXM1的这些新功能。此外，我们计划研究RB的作用，因为许多药物直接或间接地引起RB的激活，在FOXM1过表达的肿瘤中，RB会通过抑制GATA-3来支持低分化细胞的积累。进一步，我们将研究靶向FOXM1将诱导高级别肿瘤分化的假设。目标是：1。探讨FOXM1过表达在低分化乳腺癌细胞积累中的作用。2. 研究磷酸化如何影响FOXM1调节乳腺/肿瘤分化的能力。3. 探讨FOXM1/RB相互作用在低分化乳腺癌细胞积累中的作用。总的来说，这些研究