Steroid Receptor Coactivators (SRC-3) in Prostate Cancer

描述(申请人提供)：前列腺癌和乳腺癌的发生、发展和转移很大程度上受到类固醇激素、雄激素或雌激素状态的影响。这些癌症通常一开始依赖激素，然后在晚期逐渐发展到激素非依赖状态。雄激素或雌激素受体表达水平的突变和/或改变与疾病过程有关。由于辅活化子，如SRCs，是类固醇受体作用的组成部分，很可能它们也在前列腺癌和乳腺癌的形成、进展和转移中发挥作用。的确，SRC-3(PCIP、ACTR、Rac3、AIB1和TRAM-L)的表达与肿瘤的相关性非常显著。已有研究表明，SRC-3在乳腺癌、卵巢癌和胃癌患者中经常被扩增。它也在几种癌细胞系中被放大。更引人注目的是，超过60%的乳腺癌和40%的胃癌样本过度表达SRC-3。SRC-3的过度表达与预后不良、有无淋巴结和肝脏转移有关。因此，无论有没有基因扩增，SRC-3的异常表达都可能有助于细胞生长和肿瘤的形成。同样，我们的初步结果表明，SRC-3在前列腺癌患者中也过表达，特别是在晚期前列腺癌患者中。此外，我们还发现，无论AR的身高如何，SRC-3的过表达都能诱导~3H胸腺嘧啶核苷的掺入和前列腺的生长。在这项研究中，我们将扩展这项研究，检测SRC-3共激活因子在前列腺癌样本中的表达模式，并评估辅助激活因子对前列腺细胞和小鼠肿瘤形成和生长的影响和作用机制。

DESCRIPTION (provided by applicant): Initiation, progression and metastasis of prostate and breast cancers are greatly influenced by the state of steroid hormones, androgen or estrogen. These cancers usually start out as a hormone-dependent and then gradually progress to a hormone-independent state at late stages. Mutation and/or alteration of the expression levels of androgen or estrogen receptors were implicated in the disease process. Since coactivators, such as SRCs, are integrated parts of steroid receptor action, it is likely that they also play a role in prostate and breast cancer formation, progression and metastasis. Indeed, the correlation of SRC-3 (PCIP, ACTR, RAC3, AIB1 and TRAM-l) expression and cancers was very striking. It has been shown that SRC-3 is often amplified in breast, ovarian and gastric cancer patients. It is also amplified in several cancer cell lines. Even more strikingly, over 60% of breast and 40% of gastric cancer samples over-express SRC-3. Over-expression of SRC-3 was further correlated with poor prognosis and with metastasis to lymph node and liver. Thus, with or without gene amplification, aberrant expression of SRC-3 is likely to contribute to the cell growth and tumor formation. Similarly, our preliminary results indicated that SRC-3 is also over expressed in prostate cancer patients especially those of late stages. In addition, we have shown that over expression of SRC-3 induced 3H thymidine incorporation and prostate growth regardless of the AR stature. In this proposal, we will extend this study and examine the expression pattern of the SRC-3 coactivators in the prostate tumor samples and assess the effect and mechanism of action of coactivators on tumor formation and growth in prostate cells and in mice.