FoxM1 in breast cancer.

描述(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。虽然乳腺癌是一种与多种基因变化相关的异质性疾病，但乳腺癌的侵袭性与分化程度密切相关。例如，高级别肿瘤包含低分化细胞，并表现出ES(胚胎干细胞)样的基因表达特征。这些肿瘤复发的频率很高，而且是转移性的，对现有的治疗方法反应很差。这项建议的目标是研究导致高级别进展的机制。我们将检验这样的假设，即转录调控因子FOXM1在高级别、侵袭性乳腺癌的发展中起主要原因作用，以及抑制FOXM1将通过诱导肿瘤分化来阻止高级别进展。这些假说基于以下观察结果：首先，FOXM1在HER2扩增的ER-乳腺癌和三重阴性(ER-、PR-和HER2-)基底样型乳腺癌中过度表达。此外，低分化乳腺癌与FOXM1的过度表达有很强的相关性。在正常乳腺中，FOXM1的过度表达增加了腔祖细胞的数量，而FOXM1的缺失则耗尽了祖细胞/干细胞池，并增加了分化的腔细胞。FOXM1通过抑制GATA-3的表达来增加祖细胞库，GATA-3是腔分化的主要激活剂。有趣的是，FOXM1通过招募Dnmt3b诱导其启动子中CpG岛的超甲基化来抑制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。这些对管腔分化的观察表明，FOXM1在高级别进展中发挥直接作用的可能性。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的乳腺癌细胞的聚集。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导致Rb的激活，在FOXM1过表达肿瘤的情况下，Rb将通过抑制GATA-3支持低分化细胞的积累。进一步，我们将研究靶向FOXM1将在高级别肿瘤中诱导分化的假设。其目的是：1.研究FOXM1过表达在低分化乳腺癌细胞聚集中的作用。2.研究磷酸化对FOXM1的S调控乳腺/肿瘤分化能力的影响。3.探讨FOXM1/Rb相互作用在低分化乳腺癌细胞聚集中的作用。总体而言，这些研究 将对理解乳腺癌高级别进展的分子机制产生重大影响。过表达的FOXM1会招募Rb来诱导低分化肿瘤细胞的聚集，这一概念有望在临床上产生重大影响，因为许多抗癌药物会产生活性Rb，在FOXM1中过表达的肿瘤会产生细胞，导致疾病以侵袭性的形式复发。

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.