FoxM1 in tumor cell

描述(由申请人提供)： 乳腺癌仍然是女性中最致命的疾病之一。根据美国癌症协会的数据，2011年，美国约有230,480名女性被诊断出患有浸润性乳腺癌，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。CTR。这表明，军队中的女性患乳腺癌的可能性要高出20%-40%。因此，迫切需要对乳腺癌有更深入的了解和更好的治疗策略。这项建议集中在叉头盒转录因子FOXM1，它在乳腺癌的侵袭性形式中过度表达，包括基底型(S)乳腺癌。此外，FOXM1的过度表达与肿瘤的转移有关，是预后不良的生物标志物。在这项提案中，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生的机制。此外，我们还将确定靶向FOXM1的特定多肽抑制剂是否能抑制乳腺癌的转移进展。该建议是基于新发现的FOXM1在乳腺中抑制GATA-3的功能。FOXM1在管腔祖细胞中高水平表达。GATA-3对这些祖细胞具有诱导分化作用。我们将验证FOXM1在怀孕期间控制过度分化，从而在维持乳腺可塑性方面发挥重要作用的假设。GATA-3也是乳腺癌转移的抑制因子。因此，我们将研究一种假设，即抑制功能在FOXM1促进高度侵袭性乳腺癌发展的机制中起关键作用。我们鉴定了一种高度特异的FOXM1多肽抑制剂，该多肽来自肿瘤抑制基因p19ARF，它以细胞穿透性的形式(ARF多肽)抑制肝癌、P53阴性肉瘤和P53阴性淋巴瘤的转移定植。我们将研究这种多肽抑制剂是否有效地阻止转移进展和/或使乳腺癌对现有治疗方法(如紫杉醇)敏感。具体目标为：目的：研究FOXM1在乳腺中的作用。目的：探讨FOXM1在乳腺癌转移过程中的作用。目的：研究ARF衍生的FOXM1多肽抑制剂是否能抑制乳腺肿瘤的发展。这项功绩审查建议是对BLR&D RFA关于“妇女健康”的回应。随着越来越多的女性加入美国军队，退伍军人管理局在浸润性乳腺癌方面的医疗保健变得越来越重要。我们的研究将调查几个新的假说，这将对理解和治疗转移性乳腺癌有很大的帮助。

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.