The role of AP-1 transcription factor expression in androgen sensitive and androgen independent prostate cancer

Nalagatla, Sarath Krishna (2005) The role of AP-1 transcription factor expression in androgen sensitive and androgen independent prostate cancer. MD thesis, University of Glasgow.

Abstract

Development of androgen independent prostate cancer (AIPC) carries a poor prognosis. The underlying molecular mechanisms are complex and not completely understood. Androgen receptor dependent and independent mechanisms have been postulated. AP-1 is a transcription factor whose components are nuclear proteins encoded by c-Jun and c-Fos proto-oncogenes. The possible role of c-Jun and c-Fos in contributing to the development of androgen independent prostate cancer in-vivo using paired human prostate cancer tissue samples has not been studied before. Study hypothesis- AP-1 transcription factor related proteins are dysregulated in the emergence of androgen independent prostate cancer. Aims of the study- 1. To establish a paired clinical cohort of patients in which prostate cancer tissue is available at diagnosis of prostate cancer and also following the development of androgen independence in order to test the hypothesis by immunohistochemistry. 2. To evaluate the expression of AP-1 related proteins in androgen sensitive and androgen independent prostate cancer, by immunohistochemistry. We demonstrated that both androgen sensitive and androgen independent prostate cancers express c-Jun, c-Fos, phosphorylated c-Jun, PKC, COX-2 and AR proteins. A significant proportion of tumours expressed high levels of AP-1 at relapse (c-Jun 68.6%, 35/51; P-Jun, 47%, 24/51; c-Fos 40%, 20/51). An increase or no change in AP-1 (c-Jun, P-Jun & c-Fos) was observed in >80% of AlPCs. Also an increase or no change in PKC (55%), COX-2(70%) and AR (90%) protein expression in AlPC was observed. Differences in the levels of protein expression were observed as androgen sensitive prostate tumours progressed to androgen independent state. In androgen sensitive prostate tumours, we demonstrated a statistically significant correlation in expression of c-Jun, c-Fos and p-Jun proteins (table 14). In androgen independent prostate tumours c-Jun expression correlated with phosphorylated c-Jun with statistical significance (p=<0.0001). We also demonstrated that, high levels of phosphorylated c-Jun and an increase in Protein Kinase C expression at relapse were associated with a decrease in the duration of survival from relapse (p=0.003). Protein Kinase C expression correlated with COX-2 expression in both androgen sensitive as well as in androgen independent prostate tumours (p=0.014 & 0.002 respectively). Also AR protein expression correlated with phosphorylated c-Jun expression in both ASPC and AlPC (p=0.003 & 0.07 respectively). This confirms that both the proteins are involved in the progression of ASPC to AlPC as demonstrated in cell line studies [110, 204]. The study has demonstrated that AP-1 related proteins are dysregulated with the emergence of androgen independent prostate cancer in a subset of patients thus proving the hypothesis.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Dr. John Bartlett.
• Keywords: Oncology.
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Supervisor, not known
• Date of Award: 2005
• Depositing User: Enlighten Team
• Unique ID: glathesis:2005-71096
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 May 2019 10:49
• Last Modified: 02 Sep 2021 10:21
• Thesis DOI: 10.5525/gla.thesis.71096
• URI: https://theses.gla.ac.uk/id/eprint/71096