FoxM1 in breast cancer.

FoxM1 在乳腺癌中的作用。

• 批准号: 8848358
• 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/8848358
• 关键词: Age; Antineoplastic Agents; Biological Markers; Breast Cancer Cell; Cancer Etiology; Cell Culture Techniques; Cells; Cessation of life; Clinic; CpG Islands; Development; Diagnosis; Disease; ERBB2 gene; Embryo; Exhibits; Frequencies; Gene Expression Profile; Genes; Goals; Health; 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; 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。虽然它是一种与不同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，高级别肿瘤含有分化差的细胞，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，并且它们对可用的治疗反应很差。本提案的目标是调查导致高年级进展的机制。我们将检验转录调节因子FOXM 1在高级别、侵袭性乳腺癌的发展中起主要因果作用的假设，以及FOXM 1的抑制将通过诱导肿瘤分化来阻止高级别进展的假设。 这些假设基于以下观察结果：首先，FOXM 1在HER 2扩增型、ER-型和三阴性（ER-、PR-和HER 2-）基底样类型的乳腺癌中过表达。此外，低分化乳腺癌与FOXM 1过表达之间存在很强的相关性。在正常乳腺中，FOXM 1的过表达增加了管腔祖细胞的数量，而FoxM 1的缺失耗尽了祖细胞/干细胞库并增加了分化的管腔细胞。FOXM 1通过抑制加塔-3（管腔分化的主要激活剂）的表达来增加祖细胞库。有趣的是，FOXM 1通过募集DNMT 3B诱导启动子中CpG岛的超甲基化来抑制加塔-3的表达。令人惊讶的是，FOXM 1对加塔-3的抑制涉及RB肿瘤抑制蛋白。这些对管腔分化的观察表明FOXM 1在高级别进展中起直接作用的可能性。我们的机制模型是FOXM 1通过抑制加塔-3和其他管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FOXM 1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的活化，在FOXM 1过表达肿瘤的情况下，RB的活化将通过抑制加塔-3支持低分化细胞的积累。此外，我们将研究靶向FOXM 1将诱导高级别肿瘤分化的假设。目标是：1.研究FOXM 1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FOXM 1调节乳腺/肿瘤分化的能力。3.研究FOXM 1/RB相互作用在低分化乳腺癌细胞积累中的作用。 总体而言，研究 将对理解乳腺癌高级别进展的分子机制产生重大影响。预期过表达的FOXM 1募集RB以诱导低分化肿瘤细胞的积累的概念在临床中具有显著影响，因为许多抗癌药物产生活性RB，其在FOXM 1过表达的肿瘤中将产生导致疾病以侵袭性形式复发的细胞。