Stat5 as a gatekeeper in human breast cancer metastasis

Stat5作为人类乳腺癌转移的看门人

• 批准号: 6776600
• 负责人: HALLGEIR RUI
• 金额: $ 23.47万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-23 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776600
• 关键词: JAK kinase; biological signal transduction; breast neoplasms; cadherins; cancer risk; cell adhesion; cell differentiation; cell line; clinical research; disease /disorder model; enzyme activity; gene expression; genetic markers; genetically modified animals; human tissue; immunocytochemistry; laboratory mouse; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic cell; prognosis; tamoxifen; transcription factor

DESCRIPTION (provided by applicant): Each year, more than one million new cases of breast cancer are diagnosed worldwide, and an estimated 370,000 women die from breast cancer. The vast majority of fatal breast cancer cases involve metastatic spread of the primary tumor, but the metastatic process remains a complex and poorly understood process. Our long-range goal is to identify the molecular mechanisms of breast cancer progression from solitary tumor to metastasis. Based on our extensive molecular analysis of clinical human breast cancer specimens and a series of experimental breast cancer models, we now propose to test the following central hypothesis: Loss of activation of transcription factor Stat5 is a cancer progression event that favors epithelial-to-mesenchymal dedifferentiation, invasiveness, and increased metastatic potential of breast cancer cells. To accomplish the objectives of this application, we will pursue three specific aims: Aim #1: Analyze 1,300 human breast cancer specimens to establish the relationship between levels of active Stat5 and measures of tumor cell invasiveness. Aim #2: Establish whether Stat5 stimulates human breast cancer cell differentiation and adhesion, and suppresses tumor cell invasion, in vitro and in vivo. Aim #3: Determine the effect of Stat5 activation on invasion and metastasis of mouse breast cancer models in vivo. Our expectations are that by the end of the proposed project period, we will have established whether Stat5 activation status in breast cancer is a useful clinical predictor of disease progression and clinical outcome in lymph node-negative breast cancer. This is important because active Stat5 may serve as a simple immunohistochemical marker to identify node-negative breast cancer patients with excellent prognosis, permitting more individualized treatment, including selection of antiestrogen therapy. The results of this work could lead to new preventative and therapeutic strategies for primary and metastatic breast cancer.

描述（由申请人提供）：每年，全球诊断出超过一百万个新的乳腺癌病例，估计有370,000名妇女死于乳腺癌。绝大多数致命的乳腺癌病例都涉及原发性肿瘤的转移性扩散，但转移过程仍然是一个复杂且知之甚少的过程。我们的远距离目标是确定乳腺癌从孤立肿瘤发展到转移的分子机制。基于我们对临床人乳腺癌标本和一系列实验性乳腺癌模型的广泛分子分析，我们现在建议测试以下中心假设：转录因子Stat5的激活丧失是一种癌症进展事件，有利于上皮上皮到中质的替代性去分化，令人沮丧，不稳定，造成乳腺癌细胞的转移潜力增加。为了实现此应用程序的目标，我们将追求三个具体目标： AIM＃1：分析1,300个人乳腺癌标本，以建立活性STAT5水平与肿瘤细胞侵袭性度量之间的关系。 AIM＃2：确定STAT5是否刺激人类乳腺癌细胞的分化和粘附，并抑制体外和体内肿瘤细胞侵袭。 AIM＃3：确定Stat5激活对体内小鼠乳腺癌模型的侵袭和转移的影响。 我们的期望是，到拟议的项目期结束时，我们将确定乳腺癌中的STAT5激活状态是否是淋巴结阴性乳腺癌中疾病进展和临床结果的有用临床预测指标。这很重要，因为Active Stat5可以用作简单的免疫组织化学标记，以鉴定出良好的预后淋巴结阴性乳腺癌患者，允许更多个性化的治疗，包括选择抗雌激素治疗。这项工作的结果可能会导致原发性和转移性乳腺癌的新预防和治疗策略。