Involvement of growth factor receptors of the epidermal growth factor receptor family in prostate cancer development and progression to androgen independence.

The development of prostate cancer and the progression from a normal prostate epithelium to androgen-dependent cancer and eventually to hormone-refractory prostate cancer is a multistep process involving several changes in the function of different growth-regulatory signals. In the past 10 years, conflicting results on epidermal growth factor receptor (EGFR) family expression in prostate cancer have been reported. These differences may result from technical differences, lack of standardization of immunohistochemical assays, or different scoring methodologies. Recently, 4 studies have shown experimental evidence of a role of the EGFR family, particularly ErbB-2, in the development of prostate cancer and, more specifically, in the progression to hormone-refractory clinical behavior. These 4 studies were similar in some relevant aspects, such as the patient population. In fact, the patients in each study were divided into 3 groups that represent the progression of prostate cancer. In 3 of 4 studies, a statistically significant increase in ErbB-2 expression was detected by immunohistochemistry in the progression from hormone-dependent to hormone-independent disease. The expression of EGFR was also evaluated in 1 of the 4 studies. In a recent report from our group, a significant increase in EGFR expression was observed in patients treated with radical surgery, in patients who received hormonal therapy as primary therapy before radical prostatectomy, and, finally, in patients with metastatic and hormone-refractory disease. It has been proposed that EGFR family receptors and androgen receptors function synergistically in the absence of androgen suggesting cross-talk between the ErbB-2 and androgen receptor pathways, and that mitogen-activated protein kinase and phosphatidylinositol 3-kinase can be considered the transduction pathways. Finally, clinical trials are currently in progress in patients with prostate cancer testing novel agents that selectively interfere with these receptors, such as trastuzumab, an anti- ErbB-2 monoclonal antibody, and gefitinib (ZD1839, Iressa), a small-molecule selective EGFR tyrosine kinase inhibitor.