Stat5 as a gatekeeper in human breast cancer metastasis

描述（由申请人提供）：每年，全世界诊断出超过一百万例新的乳腺癌病例，估计有37万名妇女死于乳腺癌。绝大多数致命性乳腺癌病例涉及原发肿瘤的转移性扩散，但转移过程仍然是一个复杂且知之甚少的过程。我们的长期目标是确定乳腺癌从孤立性肿瘤发展到转移的分子机制。基于我们对临床人类乳腺癌标本和一系列实验性乳腺癌模型的广泛分子分析，我们现在提出测试以下中心假设：转录因子Stat5活化的丧失是一种癌症进展事件，有利于乳腺癌细胞的上皮至间充质去分化、侵袭性和转移潜力增加。为了实现本申请的目标，我们将追求三个具体目标： 目标一：分析1，300例人类乳腺癌标本，以建立活性Stat5水平与肿瘤细胞侵袭性指标之间的关系。 目标二：在体外和体内确定Stat5是否刺激人乳腺癌细胞分化和粘附，并抑制肿瘤细胞侵袭。 目的#3：确定Stat5活化对小鼠乳腺癌模型体内侵袭和转移的影响。 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局的有用临床预测因子。这一点很重要，因为活性Stat5可以作为一种简单的免疫组化标记物，用于识别预后良好的淋巴结阴性乳腺癌患者，允许更个性化的治疗，包括选择抗雌激素治疗。这项工作的结果可能会导致新的预防和治疗策略的原发性和转移性乳腺癌。

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.