Molecular regulation of breast cancer growth

乳腺癌生长的分子调控

• 批准号: 7148625
• 负责人: MARSHA A MOSES
• 金额: $ 30万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-14 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148625
• 关键词: biomarker; breast neoplasms; clinical research; human; neoplasm /cancer; neoplastic cell

DESCRIPTION (provided by applicant): Our laboratory has had a long standing interest in identifying the molecules and understanding the mechanisms that regulate tumor growth. We have recently identified the presence of NGAL (Neutrophil Gelatinase- Associated Lipocalin) both alone, and complexed to the gelatinase MMP-9, in the urine of women with breast cancer. NGAL is a member of the lipocalin family of proteins, a group of small, secreted proteins that can transport and present ligands, bind to cell-surface receptors, and form macromolecular complexes. The presence of NGAL has been correlated with breast cancer development and progression and its potential as a biomarker of human breast cancer has been suggested. We have recently demonstrated that the overexpression of NGAL in human breast cancer cells induces an EMT (Epithelial to Mesenchymal Transformation), a hallmark of cancer progression. We have found that NGAL induces the down-regulation of epithelial markers such as E-cadherin, along with a concomitant upregulation of the mesenchymal markers vimentin and fibronectin as well as inducing the development or a scattering phenotype consistent with the loss of E-cadherin- mediated cell-cell adhesion. We have also determined that the expression level of the transcription factor Slug, known to induce EMT, is increased in NGAL-expressing cells. In addition, the expression of the estrogen receptor alpha (ERalpha) was significantly downregulated by NGAL over-expression. Finally, we have demonstrated that NGAL overexpression leads to significantly increased human breast cancer cell motility and invasivity. Taken together, these data demonstrate that NGAL can induce EMT and may regulate breast cancer aggressiveness. Within the context of the Specific Aims of our proposal, we will determine the mechanism(s) by which NGAL induces EMT in breast cancer cells. These mechanistic studies will be complemented by a series of in vivo ones in which we will determine the effects of NGAL on human breast cancer progression in vivo using three complementary in vivo models. These studies will also evaluate the potential role of NGAL as a therapeutic target in the treatment of breast cancer. In the third aim of this study, we will determine whether NGAL, alone or in combination with other cancer biomarkers, may be a diagnostic and/or prognostic biomarker for breast cancer. These studies are proposed within the context of the following Specific Aims: 1. To determine the mechanism(s) by which NGAL induces an epithelial to mesenchymal transition in breast cancer cells; 2. To determine whether NGAL can promote human breast cancer progression in vivo; 3. To determine whether the presence of NGAL, alone or multiplexed with other urinary cancer biomarkers, predicts tumor presence and therapeutic efficacy in animal models of breast cancer and in human patients with breast cancer. By systematically identifying novel molecules that may be playing a role in the development of aggressive breast cancer, and by dissecting the mechanisms by which such molecules may be exerting their effects, we will have the opportunity to develop new and improved therapeutic, diagnostic and prognostic strategies that could result in significantly improved breast cancer patient survival.

描述（由申请人提供）：我们的实验室长期以来一直对识别分子和了解调节肿瘤生长的机制感兴趣。 我们最近发现，在患有乳腺癌的女性的尿液中，NGAL（中性粒细胞明胶酶相关脂质运载蛋白）单独存在，并且与明胶酶 MMP-9 复合。 NGAL 是脂质运载蛋白家族的成员，这是一组小的分泌蛋白，可以运输和呈递配体、与细胞表面受体结合并形成大分子复合物。 NGAL 的存在与乳腺癌的发生和进展相关，并且已表明其作为人类乳腺癌生物标志物的潜力。 我们最近证明，人类乳腺癌细胞中 NGAL 的过度表达会诱导 EMT（上皮间质转化），这是癌症进展的标志。 我们发现 NGAL 诱导上皮标记物（如 E-钙粘蛋白）下调，同时上调间充质标记物波形蛋白和纤连蛋白，并诱导与 E-钙粘蛋白损失一致的发育或分散表型。介导的细胞间粘附。 我们还确定，已知可诱导 EMT 的转录因子 Slug 的表达水平在表达 NGAL 的细胞中有所增加。 此外，雌激素受体α（ERα）的表达因NGAL过表达而显着下调。 最后，我们证明 NGAL 过度表达会导致人乳腺癌细胞运动性和侵袭性显着增加。 综上所述，这些数据表明 NGAL 可以诱导 EMT，并可能调节乳腺癌的侵袭性。 在我们提案的具体目标的背景下，我们将确定 NGAL 在乳腺癌细胞中诱导 EMT 的机制。 这些机制研究将得到一系列体内研究的补充，其中我们将使用三种互补的体内模型确定 NGAL 对体内人类乳腺癌进展的影响。 这些研究还将评估 NGAL 作为乳腺癌治疗靶点的潜在作用。 在本研究的第三个目标中，我们将确定 NGAL 单独或与其他癌症生物标志物组合是否可以作为乳腺癌的诊断和/或预后生物标志物。 这些研究是在以下具体目标的背景下提出的： 1. 确定 NGAL 诱导乳腺癌细胞上皮向间质转化的机制； 2. 确定NGAL在体内是否可以促进人乳腺癌进展； 3. 确定 NGAL 的存在（单独存在或与其他泌尿系癌症生物标志物复合）是否可以预测乳腺癌动物模型和人类乳腺癌患者中的肿瘤存在和治疗效果。 通过系统地识别可能在侵袭性乳腺癌发展中发挥作用的新分子，并剖析这些分子发挥作用的机制，我们将有机会开发新的和改进的治疗、诊断和预后策略这可能会显着提高乳腺癌患者的生存率。