TRANSCRIPTIONAL REGULATION OF BREAST CANCER METASTASIS

描述（由申请人提供）：乳腺癌是女性癌症死亡的第二大原因，也是女性中最常见的癌症。乳腺癌死亡的主要原因是转移，这一过程仍然知之甚少，仍然不可能准确预测患者转移形成的风险。细胞命运的特化通过建立转录因子的分级网络而发生。我们已经在全基因组微阵列筛选中鉴定出加塔-3作为青春期小鼠乳腺上皮中最高表达的转录因子，并且已经表明加塔-3在维持成年乳腺中的管腔细胞命运中起着重要作用。我们推测加塔-3可能在乳腺癌的发病机制中发挥因果作用。事实上，在人乳腺癌中，加塔-3缺失是预后不良的指标。在小鼠中，具有高加塔- 3表达的分化良好的肿瘤具有低转移倾向，而具有低加塔-3表达的分化不良的肿瘤具有更大的转移倾向。我们假设加塔-3维持乳腺肿瘤的分化，并且其缺失在恶性进展中起因果作用：在肿瘤进展期间，加塔-3维持管腔分化并抑制肿瘤细胞增殖、炎性细胞和肿瘤脉管系统的募集、肿瘤细胞播散的开始和转移能力的获得。我们将使用乳腺肿瘤易感转基因小鼠来研究癌症生长和转移，并检查加塔-3丢失和肿瘤进展之间的关系，包括炎症反应、血管生成和肿瘤细胞播散。通过去除加塔-3或改变其潜在的下游效应物，我们期望增加转移。通过重新表达加塔-3，我们希望将表型恢复为具有更好预后的表型。调控这些主调控基因的表达可能是防治乳腺癌的重要药物靶点。今年全球有超过120万名女性被诊断出患有乳腺癌，这些研究有可能提供更好的诊断，更准确地预测不良预后，并为新疗法开辟潜力。如果我们能够阻止加塔-3的丢失或在转移性肿瘤中重新激活它，我们将大大改善乳腺癌的预后，挽救数百万妇女的生命。公共卫生相关性：乳腺癌是妇女癌症死亡的第二大原因，也是妇女最常见的癌症。这项研究涉及妇女健康的一个重要方面，即加塔-3如何调节乳腺肿瘤的分化状态并防止恶性转化。如果我们能够阻止加塔-3的丢失或在转移性肿瘤中重新激活它，我们将大大改善乳腺癌的预后，挽救数百万妇女的生命。这些研究可能成为乳腺癌干预和治疗的基础，可能防止癌前病变恶化和转移。

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.