The role of steroid receptor coactivator (SRC) in the development of prostate cancer

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Androgen receptor (AR) is a nuclear receptor, which regulates important biological events such as development of the normal prostate gland and prostate cancers. Once AR is bound to its cognate hormone, it recruits a diverse group of proteins called coactivators to regulate expression of target genes. Steroid Receptor Coactivator (SRC) is a member of the p160 family of nuclear receptor coactivators, which consists of SRC-1,SRC-2 and SRC-3. Previous studies indicate that SRC-3 is often amplified or overexpressed in some human cancers. However, the mechanisms of SRC-3-mediated growth regulation remain unclear. In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell.We examined the expression level of SRC-1,SRC-2 and SRC-3 in 70 prostate cancer patients' samples and human prostate cancer cell lines by immunohistochemistry and Western analysis, respectively. It was found that 47% of human prostate cancer samples (N=70) overexpresses SRC-3 in the tumor area but not in the adjacent normal area. In general, the over-expression of SRC-3 correlated with patients' characteristics such as recurrence and hormone dependency. In addition, we established stable LNCaP and PC3 cell lines over-expressing SRC-3. These cell lines were used to investigate the effect of SRC-3 over-expression in prostate cancer cell growth. It was observed a significant increase in cell growth of stable cell lines with overexpression of SRC-3. And overexpression of SRC-3 modulated the AKT signaling pathway, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size. In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA (siRNA) decreases cell growth, leading to a smaller cell size.These findings suggest that the expression levels of SRC-3 may be an additional biomarker for the tumor formation, metastasis and androgen dependency in prostate cancers.