Prostate cancer is the second leading cause of cancer death in men. In the United States alone, 192,280 new cases of prostate cancers were diagnosed in 2009 and among them around 27,360 deaths occurred. One of the biggest challenges we face in prostate cancer is determining if the cancer is aggressive. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate. Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for human prostate cancer intervention. However, despite being the mainstay of prostate cancer detection, the value of PSA screening is still debated. In particular, there is a growing concern regarding the over diagnosis of potentially indolent disease [
1]. Therefore, there remains an urgent need for more accurate biomarkers to diagnose aggressive prostate cancer. Thus, identification of new molecular markers/targets for aggressive prostate cancer is important in order to improve early detection of the aggressive disease and to develop new therapeutic regimens.
Progression of prostate cancer from focal, androgen-dependent lesions to androgen-independent, metastatic cancer requires deregulation of growth control, invasiveness and cell motility. Abundant evidence demonstrates roles for Ets transcription factors in many cancers including prostate. Prostate-derived Ets factor (PDEF), first described nine years ago as preferentially binding to the noncanonical Ets core sequence GGAT [
2], has recently received considerable attention due to its potential importance in regulating cell motility and invasion [
3‐
5]. Recently, proteomic analysis of PDEF overexpressing cells revealed 286 proteins in the PDEF-associated protein complex in breast cancer [
6]. Thus interaction of PDEF with other partner proteins could help in finding their role in maintenance of malignant phenotype. Published literature concerning experimental manipulation of PDEF expression is paradoxical and limited to tissues of high epithelial content, notably prostate, breast, ovary and colon [
7,
8]. PDEF expression has been both positively [
3,
9] and negatively [
10] correlated with breast cancer grade at mRNA or protein levels. It is important to note that PDEF mRNA and protein levels do not always correlate, which may have led to different conclusions in some of the studies examining PDEF expression in primary tumors. Turner et al. [
4] found that introducing PDEF into invasive breast cancer cell lines reduced their invading ability. Similarly, siRNA-mediated knockdown of PDEF in MCF7 cells increased their ability to migrate in the Transwell assay. Besides its role in cancer metastasis, PDEF expression was also correlated with changes in the actin cytoskeleton and focal adhesion localization, and loss of cellular polarity. Ghadersohi et al. [
10] silenced PDEF expression in MCF7 cells, and found that such cells showed greatly accelerated xenograft tumor formation in SCID mice. By contrast, Gunawardane et al. [
3] showed that increasing expression of PDEF increased their ability to migrate in a Transwell assay and stimulated colony formation in soft agar. This group also identified a canonical MAP kinase phosphorylation site at T50 (PAT
50P) and showed that mutation to alanine at this site abolished all the effects they observed. To date there are few data available formally correlating PDEF expression in maintenance of prostate malignant phenotype. Two published studies, one with a prostate cancer cell-line [
5] and another with clinical samples from prostate [
11] reached opposite conclusions with respect to the role of PDEF in prostate cancer. Clearly additional studies are necessary to evaluate role of PDEF in prostate cancer biology.
In the current studies, we report here that PDEF expression is lost, whereas MMP9 expression increased with the aggressive behavior of prostate cancer. Overexpression of PDEF in PC3 cells strongly inhibits colony formation, cell migration and invasion, and increased cell adherence. Furthermore, re-introduction of PDEF in PC3 cells led to changes in actin cytoskeleton, altered focal adhesion kinase activity, and reestablished cell polarity in these cultures as indicated by induction of less invasive spheroid-like structures in three-dimensional culture, Moreover, PDEF expression downregulates MMP9 expression, and its promoter activity in PC3 cells. Thus, consideration of both PDEF and MMP9 may have a better prognosis value for determining the aggressive phenotype of prostate cancer.