Stat5 as a gatekeeper in human breast cancer metastasis

描述（由申请人提供）：每年，全球有超过100万例乳腺癌新病例被诊断出来，估计有37万妇女死于乳腺癌。绝大多数致死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，我们现在提议测试以下中心假设：转录因子Stat5激活的丧失是癌症进展事件，有利于乳腺癌细胞的上皮到间质去分化、侵袭性和转移潜力的增加。为了实现此应用程序的目标，我们将追求三个具体目标：

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.