TRANSCRIPTIONAL REGULATION OF BREAST CANCER METASTASIS

描述(申请人提供)：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。乳腺癌的主要死亡原因是转移，这一过程仍然知之甚少，而且仍然不可能准确预测患者转移形成的风险。细胞命运的指定是通过建立转录因子的分级网络来实现的。我们已经在全基因组微阵列筛选中确定GATA-3是青春期小鼠乳腺上皮中表达最高的转录因子，并表明GATA-3在维持成人乳腺管腔细胞命运方面发挥着重要作用。我们推测GATA-3可能在乳腺癌的发病机制中起着因果作用。事实上，在人类乳腺癌中，GATA-3的缺失是预后不良的一个指标。在小鼠中，高表达GATA-3的高分化肿瘤转移倾向低，而低分化低表达GATA-3的肿瘤转移倾向更大。我们推测，GATA-3维持乳腺肿瘤的分化，其缺失在恶性进展中起因果作用：在肿瘤进展过程中，GATA-3维持管腔分化，抑制肿瘤细胞增殖，抑制炎症细胞和肿瘤血管的募集，肿瘤细胞扩散的开始和转移能力的获得。我们将使用易患乳腺癌的转基因小鼠来研究肿瘤的生长和转移，并研究GATA-3缺失与肿瘤进展的关系，包括启动炎症反应、血管生成和肿瘤细胞扩散。通过移除GATA-3或改变其潜在的下游效应因子，我们预计会增加转移。通过重新表达GATA-3，我们希望将表型恢复为预后更好的表型。调控这些主控基因的表达可能是防治乳腺癌的重要药物靶点。今年全球有120多万女性被确诊，这些研究有可能提供更好的诊断，更准确地预测不良预后，并开启新疗法的潜力。如果我们能防止GATA-3的丢失或在转移的肿瘤中重新激活它，我们将极大地改善乳腺癌的预后，拯救数百万女性的生命。公共卫生相关性：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。这项研究解决了妇女健康的一个重要方面，即GATA-3如何调节乳腺肿瘤的分化状态和防止恶性转化。如果我们能防止GATA-3的丢失或在转移的肿瘤中重新激活它，我们将极大地改善乳腺癌的预后，拯救数百万女性的生命。这些研究可能形成乳腺癌干预和治疗的基础，潜在地防止癌前病变变得恶性和转移。

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. The primary cause of death in breast cancer is metastasis, a process that is still poorly understood, and it is still not possible to accurately predict the risk of metastasis formation in patients. The specification of cell fate occurs through the establishment of hierarchical networks of transcription factors. We have identified GATA-3 in a genome-wide microarray screen as being the most highly expressed transcription factor in the mammary epithelium of pubertal mice and have shown that GATA-3 plays a fundamental role in the maintenance of the luminal cell fate in the adult mammary gland. We hypothesize that GATA-3 may be playing a causal role in the pathogenesis of breast cancer. Indeed in human breast cancer GATA-3 loss is an indicator of poor prognosis. In mouse, well differentiated tumors with high GATA- 3 expression have a low propensity for metastasis, whereas poorly differentiated tumors with low GATA-3 expression have a greater propensity for metastasis. We postulate that GATA-3 maintains the differentiation of breast neoplasms, and its loss plays a causal role in malignant progression: During neoplastic progression, GATA-3 maintains luminal differentiation and suppresses tumor cell proliferation, the recruitment of inflammatory cells and tumor vasculature, the onset of tumor cell dissemination and the acquisition of metastatic capability. We will use mammary tumor prone transgenic mice to study cancer growth and metastasis and examine the relationship between GATA-3 loss and tumor progression, including mounting an inflammatory response, angiogenesis and tumor cell dissemination. By removing GATA-3 or altering its potential downstream effectors we expect to increase metastasis. By re-expressing GATA-3 we hope to revert the phenotype to one with a better prognosis. Regulating the expression of these master regulatory genes may represent an important drug target for prevention and cure of breast cancer. With more than 1.2 million women diagnosed this year worldwide, these studies have the potential of providing better diagnosis, more accurate predicting of poor prognosis and open the potential for new therapies. If we could prevent the loss of GATA-3 or reactivate it in metastasizing tumors we would greatly improve breast cancer outcome and save the lives of millions of women. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, that of how GATA-3 regulates the differentiated state of breast tumors and prevents malignant conversion. If we could prevent the loss of GATA-3 or reactivate it in metastasizing tumors we would greatly improve breast cancer outcome and save the lives of millions of women. These studies may form the basis of intervention and therapy in breast cancer, potentially preventing premalignant lesions from becoming malignant and metastasizing.