FoxM1 in tumor cell

肿瘤细胞中的 FoxM1

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9339464
• 关键词: Alpha Cell; American Cancer Society; Biological Markers; Development; Diagnosis; Disease; FOXM1 gene; Gland; Head; Health; Healthcare; Lactation; Lead; Lymphoma; Maintenance; Malignant neoplasm of liver; Mammary Neoplasms; Mammary gland; Medical center; Metastatic breast cancer; Metastatic to; Neoplasm Metastasis; Paclitaxel; Peptides; Physicians; Play; Population; Pregnancy; Process; Repression; Resistance; Role; Stem cells; TP53 gene; Testing; Therapeutic; Tumor Suppressor Proteins; Tumor-Derived; Tumorigenicity; Woman; Women' s Health; age group; base; breast cancer survival; cancer stem cell; gene repression; inhibitor/antagonist; malignant breast neoplasm; neoplastic cell; novel; outcome forecast; overexpression; p19ARF; progenitor; public health relevance; response; sarcoma; transcription factor; tumor; tumor progression

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）： 乳腺癌仍然是妇女最致命的疾病之一。根据美国癌症协会的数据，2011年美国约有230，480名女性被诊断患有浸润性乳腺癌，当年约有40，000人死亡。此外，沃尔特里德陆军医学中心2009年的一项研究。研究表明，军队中的女性患乳腺癌的可能性要高出20-40%。因此，迫切需要更好地了解乳腺癌和更好的治疗策略。这项提案的重点是叉头盒转录因子FoxM 1，它在乳腺癌的侵袭性形式中过度表达，包括基底型乳腺癌。此外，FoxM 1的过表达与转移一致，并且是预后不良的生物标志物。在这项提案中，我们计划评估FoxM 1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，我们将确定是否使用特定的肽抑制剂靶向FoxM 1抑制乳腺癌的转移进展。该提议基于FoxM 1在乳腺中抑制加塔-3的新发现的功能。FoxM 1在管腔祖细胞中以高水平表达。加塔-3诱导这些祖细胞的分化。我们将测试的假设，FoxM 1控制过度分化在怀孕期间，从而发挥了重要作用，在维持乳腺的可塑性。加塔-3也是乳腺癌转移的抑制因子。因此，我们将研究的假设，即抑制功能是关键的机制，FoxM 1有助于发展的高度侵袭性乳腺癌。我们已经表征了来自肿瘤抑制因子p19 ARF的FoxM 1的高度特异性肽抑制剂，其以细胞穿透形式（ARF肽）抑制肝癌、p53无效肉瘤和p53无效淋巴瘤的转移性定殖。我们将研究这种肽抑制剂是否有效地阻止转移进展和/或使乳腺癌对现有疗法（例如紫杉醇）敏感。具体目标是：Aim 1：研究FoxM 1在乳腺中的作用。 目的2：探讨FoxM 1在乳腺癌转移进展中的作用。 目的3：研究ARF衍生的FoxM 1肽抑制剂是否抑制乳腺肿瘤进展。这一价值审查提案是对BLR&D RFA关于“妇女健康”的回应。随着越来越多的女性进入美国陆军，退伍军人事务部关于浸润性乳腺癌的医疗保健变得越来越重要。我们的研究将探讨几个新的假说，这将是深刻的理解和转移性乳腺癌的治疗。