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）：乳腺癌是各个年龄段女性与癌症相关死亡的主要原因。尽管诊断和治疗取得了进步，但死亡率仍然很高。虽然这是一种与遗传变化不同的异质疾病，但乳腺癌的侵略性与分化水平密切相关。例如，高级肿瘤包含分化较差的细胞，并且表现出ES（胚胎茎）（例如基因表达特征）。这些肿瘤以高频复发，它们是转移性的，对可用疗法的反应较差。该提案的目的是研究导致高级进展的机制。我们将测试转录调节剂FOXM1在高级，侵略性乳腺癌的发展中起主要因果作用的假设，并且对FOXM1的抑制会通过诱导肿瘤分化来阻碍高级进展。 这些假设基于以下观察结果，首先，FOXM1在HER2扩增，ER-和三重阴性（ER-，PR-和HER2-）基底样乳腺癌中过度表达。此外，分化较差的乳腺癌与FOXM1的过表达之间存在很强的相关性。在正常的乳腺中，FOXM1的过表达增加了腔内祖细胞的种群，而FOXM1的缺失会耗尽祖细胞/茎池并增加分化的腔细胞。 FOXM1通过抑制腔分化的主激活剂GATA-3的表达来增加祖细胞池。有趣的是，FOXM1通过募集DNMT3B在启动子中诱导CpG岛的高甲基化来抑制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。这些对腔分化的观察结果表明，FOXM1在高级进程中起着直接作用的可能性。我们的机械模型是，FOXM1通过抑制GATA-3和其他腔内因子来促进分化较差的乳腺癌细胞的积累。我们将同时使用细胞培养和小鼠模型来研究FOXM1的这些新功能。同样，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，如果FOXM1过表达肿瘤，这将通过抑制GATA-3来支持分化差的细胞的积累。此外，我们将研究靶向FOXM1将诱导高级肿瘤分化的假设。目的是：1。研究FOXM1过表达在分化较差的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。研究FOXM1/RB相互作用在分化较差的乳腺癌细胞积累中的作用。 总体而言，研究 将对乳腺癌高度进展的分子机制的理解产生重大影响。预计过表达FOXM1招募RB以诱导不良分化肿瘤细胞的积累的观念预计在临床中会产生重大影响，因为许多抗癌药物会产生活性RB，在FOXM1中，这种RB会产生过表达的肿瘤，会产生侵略性形式的疾病复发的细胞。