FoxM1 in tumor cell

肿瘤细胞中的 FoxM1

基本信息

批准号：
9339464
负责人：
Pradip Raychaudhuri
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2019-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Breast cancer remains one of the deadliest diseases in women. According to American Cancer Society about 230,480 women in the US were diagnosed with invasive breast cancer in 2011 and about 40,000 died in that year. Also, a 2009 study by the Walter Reed Army Med. Ctr. suggested that women in the army are 20-40% more likely to develop breast cancer. Therefore, a greater understanding of breast cancer and better therapeutic strategies are urgently needed. This proposal focuses on the fork-head box transcription factor FoxM1 that is over-expressed in the aggressive forms of breast cancers, including the Basal type(s) of breast cancer. Moreover, over-expression of FoxM1 coincides with metastasis and is a biomarker for poor prognosis. In this proposal, we plan to evaluate the functions of FoxM1 in normal mammary gland as well as in the mechanisms that lead to the development of aggressive breast cancer. In addition, we will determine whether targeting FoxM1 using a specific peptide-inhibitor inhibits metastatic progression of breast cancer. The proposal is based on a newly discovered function of FoxM1 in repression of GATA-3 in mammary gland. FoxM1 is expressed at a high level in the luminal progenitor cells. GATA-3 induces differentiation of those progenitors. We will test the hypothesis that FoxM1 controls excessive differentiation during pregnancy, and thus plays an important role in maintaining plasticity of the mammary gland. GATA-3 also is a suppressor of metastasis in breast cancer. Therefore, we will investigate the hypothesis that the repression function of is critical to the mechanism by which FoxM1 contributes to the development of highly aggressive breast cancer. We have characterized a highly specific peptide inhibitor of FoxM1 derived from the tumor suppressor p19ARF that in a cell- penetrating form (ARF-peptide) inhibits metastatic colonization of liver cancer, p53-null sarcoma and p53-null lymphoma. We will investigate whether that peptide-inhibitor efficiently blocks metastatic progression and/or sensitizes breast cancers to available therapies, such as Taxol. The specific aims are: Aim1: Investigate the roles of FoxM1 in mammary gland. Aim2: Investigate the roles of FoxM1 in the metastatic progression of breast cancer. Aim3: Investigate whether the ARF-derived peptide inhibitor of FoxM1 inhibits mammary tumor progression. This merit review proposal is in response to BLR&D RFA on "Women's Health". As more women are entering the US Army, health care at the VA with regards to invasive breast cancer is becoming increasingly significant. Our studies will investigate several novel hypotheses, which will be insightful in understanding and in therapy of metastatic breast cancers.

描述（由申请人提供）：乳腺癌仍然是女性最致命的疾病之一。根据美国癌症协会的数据，2011年，美国约有230,480名妇女被诊断出患有侵入性乳腺癌，当年约有40,000名死亡。另外，沃尔特·里德（Walter Reed）军事医学（Walter Reed Army Med）2009年的一项研究。 CTR。建议陆军妇女患乳腺癌的可能性高20-40％。因此，迫切需要对乳腺癌和更好的治疗策略有更多的了解。该提案的重点是以侵略性形式的乳腺癌（包括乳腺癌的基础类型）过表达的叉子盒转录因子FOXM1。此外，FOXM1的过表达与转移相吻合，并且是预后不良的生物标志物。在此提案中，我们计划评估FOXM1在正常乳腺中的功能以及导致侵袭性乳腺癌发展的机制。此外，我们还将确定使用特定的肽抑制剂靶向FOXM1是否抑制乳腺癌的转移性进展。该提案基于FOXM1在乳腺中GATA-3抑制中的新发现的功能。 FOXM1在腔内祖细胞中以高水平表达。 GATA-3诱导这些祖细胞的分化。我们将检验以下假设：FOXM1控制怀孕期间过度的分化，因此在维持乳腺的可塑性中起着重要作用。 GATA-3也是乳腺癌转移的抑制剂。因此，我们将研究以下假设：FOXM1促进高度侵略性乳腺癌的机制至关重要。我们已经表征了源自肿瘤抑制剂p19arf的FOXM1的高度特异性肽抑制剂，该抑制剂p19arf以细胞穿透形式（ARF肽）抑制肝癌的转移性定殖，p53-null肉瘤和p53-null lymphoma。我们将研究该肽抑制剂是否有效阻断转移性进展和/或使乳腺癌对可用疗法（例如紫杉醇）的敏感性。具体目的是：AIM1：研究FOXM1在乳腺中的作用。 AIM2：研究FOXM1在乳腺癌转移性进展中的作用。 AIM3：研究FOXM1的ARF衍生肽抑制剂是否抑制乳腺肿瘤进展。该优点审查提案是对Blr＆d RFA的“妇女健康”的回应。随着越来越多的妇女进入美国陆军，弗吉尼亚州的医疗保健在侵入性乳腺癌方面变得越来越重要。我们的研究将研究一些新的假设，这将在理解和治疗转移性乳腺癌方面有见地。