Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

Abstract

Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve 'cross-talk' between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa.

Dihydrotestosterone upregulates the expression of epidermal growth factor receptor and ERBB2 in androgen receptor-positive bladder cancer cells

“…In this study, we provide evidence that androgens regulate EGFR and ERBB2 expression via the AR pathway in bladder cancer cells. In prostate cells, the AR likely has opposing effects on the regulation of EGFR expression: downregulation in benign cells and upregulation in malignant cells (Brass et al 1995, Itoh et al 1998, Traish & Morgentaler 2009). In prostate cancer cells, androgens were also reported to reduce EGFR protein expression (Mukherjee & Mayer 2008).…”

“…Ligand-activated AR is known to have dual functions in regulating target proteins either by increasing transcription or by decreasing degradation. The regulation of EGFR expression by androgens was shown to be at the transcriptional level in prostate cancer cell lines (Traish & Morgentaler 2009). Our protein stability assays showing marginal effects of androgen suggest that the AR functions only as a transcription factor in regulation of both EGFR and ERBB2 in bladder cancer cells.…”

Linc00963: A novel, long non-coding RNA involved in the transition of prostate cancer from androgen-dependence to androgen-independence

“…Furthermore, previous clinical studies suggested a correlation of EGFR expression with androgen-independence (6). More importantly, EGFR itself may be under the regulation of androgen signaling pathway, being negative in normal prostate cells but positive in prostate cancer cells, especially in androgen-independent cancer cells (7). In an effort to overcome castration-resistance, trials combining EGFR or dual kinase inhibitors with other novel agents are in development (8).…”

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

“…To date, no effective therapy allows the abrogation of prostate cancer's progression to advanced, invasive forms. Recent evidence suggests that acquisition of androgen independence may be due to upregulation of growth factor/receptor signaling pathways, principally the epidermal growth factor receptor (EGFR) (Kambhampati et al, 2005;Traish and Morgentaler, 2009), making EGFR an attractive target for therapeutic intervention. However, the exact contribution that EGFR makes to prostate cancer progression remains unclear.…”