Interplay of Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 3 in Prostate Cancer: Beyond Androgen Receptor Transactivation

SIMPLE SUMMARY: Androgen receptor (AR) signaling mainly controls prostate cancer (PCa) growth. Hence, the conventional regimen for PCa includes androgen deprivation therapy (ADT) or antiandrogen in order to reduce PCa recurrence. However, castration-resistant prostate cancer (CRPC) is insensitive to environmental androgen via self-supplementation of androgen or inactivation of AR signaling. Accordingly, CRPC has limited treating options and their outcome is poor. Previous studies reveal that forming CRPC needs to maintain cell growth under low AR signaling conditions and to mitigate AR dependency by differentiation. Previous studies show that the epidermal growth factor (EGFR) and signal transducer and activator of transcription 3 (STAT3) participate in the maintenance of PCa growth under androgen ablation. We have found a novel mechanism in which EGFR cooperates with STAT3 and initiates neuroendocrine differentiation. This review aims to summarize the recent findings on EGFR and STAT3 in CRPC induction and discuss the unsolved issues therein. ABSTRACT: Prostate cancer (PCa) is one of the most common cancers in the world and causes thousands of deaths every year. Conventional therapy for PCa includes surgery and androgen deprivation therapy (ADT). However, about 10–20% of all PCa cases relapse; there is also the further development of castration resistant adenocarcinoma (CRPC-Adeno) or neuroendocrine (NE) PCa (CRPC-NE). Due to their androgen-insensitive properties, both CRPC-Adeno and CRPC-NE have limited therapeutic options. Accordingly, this study reveals the inductive mechanisms of CRPC (for both CRPC-Adeno and CRPC-NE) and fulfils an urgent need for the treatment of PCa patients. Although previous studies have illustrated the emerging roles of epidermal growth factor receptors (EGFR), signal transducer, and activator of transcription 3 (STAT3) signaling in the development of CRPC, the regulatory mechanisms of this interaction between EGFR and STAT3 is still unclear. Our recent studies have shown that crosstalk between EGFR and STAT3 is critical for NE differentiation of PCa. In this review, we have collected recent findings with regard to the involvement of EGFR and STAT3 in malignancy progression and discussed their interactions during the development of therapeutic resistance for PCa.