The Role of SRC-1 in Breast Cancer

描述(申请人提供)：大多数乳腺癌患者死于癌症转移而不是原发肿瘤生长。然而，由于缺乏合适的动物模型和识别转移特异性基因的困难，我们对乳腺癌转移调控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活化子-1(SRC-1)在转移性人类癌症中过表达，提示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，我们产生了SRC-1基因敲除小鼠。我们发现，SRC-1在小鼠体内的失活显著抑制了癌基因诱导的乳腺癌转移，而不影响原发乳腺癌的形成和生长。移植分析进一步表明，SRC-1在乳腺肿瘤细胞中的自主功能抑制了乳腺肿瘤的转移。这些发现清楚地表明，SRC-1是乳腺癌转移的一个新的关键调节因子。本项目将研究SRC-1在乳腺癌转移中的特殊作用和调控机制。首先，我们将建立乳腺上皮细胞特异性过表达SRC-1的转基因小鼠，以研究SRC-1过表达是否促进体内癌基因诱导的乳腺癌转移。我们还将研究在未转移的人乳腺癌细胞中过表达SRC-1是否会增强其在培养中的运动性和侵袭性，并将这些未转移的细胞转变为裸鼠体内的转移细胞。其次，我们计划通过检测SRC-1在转移性人乳腺癌细胞中的敲除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，我们将研究几个受SRC-1调控的基因在乳腺癌转移中的作用。最后，我们将试图了解SRC-1调控其与乳腺癌转移相关的靶基因的调控机制。通过基因芯片分析对SRC-1靶基因进行了鉴定。我们相信，这些精心设计的研究将提供一条新的研究途径，以了解乳腺癌转移的某些基本方面，并导致识别新的分子标志物和可用药靶点，以便更好地诊断、预后和治疗乳腺癌转移。

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.