The Role of EGFR in Prostate Cancer Progression and Combination Therapy(2/3)

Dysregulation of the epidermal growth factor receptor (EGFR) signaling axis enhances metastatic capability to bone in many solid cancers. However the orderly sequence of events downstream of altered EGFR signal transduction that leads to lethal metastatic prostate cancer is unclear. We have previously shown that miR-1 is a tumor suppressor in prostate cells, and its expression is correlated with reduced metastatic potential. Here we propose a role for EGFR in tumor progression directly through EGFR translocation that regulates primary miR-1-1 transcription and leads to downregulation of miR-1. The first aim of this study will investigate the biological functions of nuclear EGFR that regulate the expression of miR-1 and enhance the metastatic potential of advanced prostate cancer. In support of prostate cancer tumorigenesis, miR-1 has been found to be differentially downregulated in prostate cancer clinical cases relative to normal prostate tissue. It is not clear how miR-1 expression is related to prostate cancer metastasis, and few downstream targets are described for prostate cancer. TWIST1 has been shown to be expressed at high levels in prostate cancer and found to associate with EGFR mutation in breast cancer. However, the specific connotation of TWIST1 and EGFR pathway in metastatic prostate cancer remains elusive. Our preliminary results found that TWIST1 is a candidate target gene for miR-1. Following bioinformatic analysis of clinical gene expression databases, our results suggest that the expression of decreased miR-1 and increased TWIST1, correlate to activated EGFR signaling in prostate cancer. The second aim of this study will elucidate the regulatory mechanisms of miR-1 that target TWIST1 and investigate the clinical relevance of miR-1 in TWIST1-activated prostate cancer. Most therapeutic failures in metastatic cancers are attributed to drug resistance. Cancer stem cells (CSCs), including those of advanced prostate cancer, are a suggested reason for tumor resistance towards conventional tumor therapy. Our research group has tested the effect of Berberis libanotica Ehrenb (BLE) extract on prostate cancer cells and our data indicated that this extract induced significant reduction in cell viability and sufficient to eradicate the self-renewal ability of highly resistant CSCs. It has been described that overexpression of miR-1 in lung cancer cells contributed to chemotherapy sensitivity. However, the role of miR-1 targets in anti-apoptosis signaling, and how its overexpression contributes to the induction of apoptosis in chemoresistant prostate cancer cells remain largely unknown. Understanding the intrinsic molecular mechanisms of resistance to this drug in prostate cancer, especially as miR-1 regulatory mechanism, is a major objective of our proposed studies. Thus, the third aim of this study will explore the therapeutic roles of Berberis libanotica Ehrenb (BLE) that associates with miR-1 expression and contributes to sensitivity of drug treatment in metastatic prostate cancer. In this three-year research project, we plan to expand on the existence of an EGFR, miR-1, and TWIST1 regulatory network where the induction of TWIST1 resulted in increased bone metastasis and chemoresistance that is linked to dysregulation of the EGFR signaling pathway through inactivation of miRs.