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.
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