Stat5 as a gatekeeper in human breast cancer metastasis

描述(申请人提供)：全世界每年有100多万新的乳腺癌病例被诊断出来，估计有37万妇女死于乳腺癌。绝大多数致命的乳腺癌病例涉及原发肿瘤的转移扩散，但转移过程仍然是一个复杂且鲜为人知的过程。我们的长期目标是确定乳腺癌从单发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，我们现在建议检验以下核心假设：转录因子Stat5的激活缺失是一种癌症进展事件，有利于乳腺癌细胞上皮到间充质去分化、侵袭性和转移潜能的增加。为了实现本应用程序的目标，我们将追求三个具体目标： 目的#1：分析1300例人乳腺癌标本，建立其活性STAT5水平与肿瘤细胞侵袭力之间的关系。 目的#2：建立STAT5在体内外是否促进人乳腺癌细胞分化和黏附，抑制肿瘤细胞侵袭。 目的#3：探讨Stat5激活对小鼠乳腺癌模型体内侵袭转移的影响。 我们的期望是，在拟议的项目期结束时，我们将确定乳腺癌中的Stat5激活状态是否可以作为淋巴转移阴性乳腺癌的疾病进展和临床预后的有用临床预测指标。这一点很重要，因为激活的Stat5可以作为一种简单的免疫组织化学标记物来识别预后良好的淋巴结阴性乳腺癌患者，允许进行更多的个体化治疗，包括选择抗雌激素治疗。这项工作的结果可能导致对原发和转移性乳腺癌的新的预防和治疗策略。

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.