The Role of SRC-1 in Breast Cancer

SRC-1 在乳腺癌中的作用

• 批准号: 7033788
• 负责人: JIANMING XU
• 金额: $ 26.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033788
• 关键词: breast neoplasms; human; metastasis; neoplasm /cancer; role

DESCRIPTION (provided by applicant): The majority of breast cancer patients die of cancer metastasis rather than primary tumor growth. However, we know very little about the mechanisms and the gene networks responsible for regulation of breast cancer metastasis due to the lack of appropriate animal models and the difficulties to identify metastasis-specific genes. Recently, we and others observed that the steroid receptor coactivator-1 (SRC-1) is overexpressed in metastatic human cancers, suggesting it may play an important role in breast cancer metastasis. To study the role of SRC-1 in mammary gland development and tumorigenesis, we have generated SRC-1 knockout mice. We showed that inactivation of SRC-1 in mice drastically suppresses oncogene-induced breast cancer metastasis without affecting the primary breast tumor formation and growth. Transplantation analysis further revealed that the suppression of mammary tumor metastasis is accredited to the autonomous function of SRC-1 in the mammary tumor cells. These findings clearly indicate that SRC-1 is a novel key regulator of the breast cancer metastasis. This project will characterize the specific contribution and regulatory mechanism of SRC-1 in breast cancer metastasis. First, we will generate transgenic mice with mammary epithelial cell-specific overexpression of SRC-1 to address whether SRC-1 overexrpession promotes oncogene-induced breast cancer metastasis in vivo. We also will investigate whether overexpression of SRC-1 in non-metastatic human breast cancer cells will enhance their motility and invasive behavior in culture and change these non-metastatic cells into metastatic cells in nude mice. Second, we plan to study SRC-1 as a target for inhibiting breast cancer metastasis by examining whether knockdown of SRC-1 in metastatic human breast cancer cells will blockade or reduce their metastasis capability. Third, we will investigate the roles of several SRC-1-regulated genes in breast cancer metastasis. Finally, we will try to understand the regulatory mechanisms by which SRC-1 regulates its target genes relevant to breast cancer metastasis. These SRC-1 target genes were identified by gene array analysis. We believe that these carefully designed studies will provide a new avenue of research to understand certain essential aspects of breast cancer metastasis and lead to identification of new molecular markers and drugable targets for better diagnosis, prognosis and treatment of breast cancer metastasis.

描述（由申请人提供）：大多数乳腺癌患者死于癌症转移而不是原发性肿瘤生长。然而，由于缺乏合适的动物模型以及识别转移特异性基因的困难，我们对调控乳腺癌转移的机制和基因网络知之甚少。最近，我们和其他人观察到类固醇受体辅激活因子-1 (SRC-1) 在人类转移性癌症中过度表达，表明它可能在乳腺癌转移中发挥重要作用。为了研究SRC-1在乳腺发育和肿瘤发生中的作用，我们培育了SRC-1基因敲除小鼠。我们发现，小鼠中 SRC-1 的失活可显着抑制癌基因诱导的乳腺癌转移，而不影响原发性乳腺肿瘤的形成和生长。移植分析进一步表明，乳腺肿瘤转移的抑制归因于乳腺肿瘤细胞中SRC-1的自主功能。这些发现清楚地表明SRC-1是乳腺癌转移的新型关键调节因子。该项目将表征SRC-1在乳腺癌转移中的具体贡献和调控机制。首先，我们将产生乳腺上皮细胞特异性过度表达 SRC-1 的转基因小鼠，以探讨 SRC-1 过度表达是否会促进癌基因诱导的体内乳腺癌转移。我们还将研究在非转移性人乳腺癌细胞中过度表达SRC-1是否会增强其在培养物中的运动性和侵袭行为，并将这些非转移性细胞转变为裸鼠中的转移性细胞。其次，我们计划通过检查转移性人乳腺癌细胞中SRC-1的敲低是否会阻断或降低其转移能力来研究SRC-1作为抑制乳腺癌转移的靶点。第三，我们将研究几个SRC-1调节基因在乳腺癌转移中的作用。最后，我们将尝试了解SRC-1调节其与乳腺癌转移相关的靶基因的调节机制。通过基因阵列分析鉴定了这些SRC-1靶基因。我们相信，这些精心设计的研究将为了解乳腺癌转移的某些重要方面提供新的研究途径，并确定新的分子标记和药物靶标，以更好地诊断、预后和治疗乳腺癌转移。