Deciphering the Regulation and Role of Protein Tyrosine Phosphatase 1B in Prostate Cancer PDF Download

Author: David Labbé
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Languages : en
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Book Description
"Despite the early diagnosis and efficient treatment of most early-stage tumors, prostate cancer (PCa) remains the second leading cause of cancer-related deaths in North American men. This reflects the use of androgen deprivation therapy, initially described in 1941, as the standard treatment for patients diagnosed with advanced disease despite the eventual development of incurable castration-resistant metastatic cancer. Therefore there is an urgent need for novel and innovative approaches to effectively treat this disease. Elevated tyrosine phosphorylation is a major contributor to tumor progression. As such, many tyrosine kinase inhibitors are presently being tested for the treatment of advanced PCa in clinical trials. However, one largely unexplored mechanism in prostate tumorigenesis is the regulation of tyrosine phosphorylation by classical protein tyrosine phosphatases. Owing to the putative oncogenic role of the protein tyrosine phosphatase 1B (PTP1B) in various cancers, the objective of my doctoral research was to investigate its regulation and role in PCa. First, we identified the androgen receptor (AR) as a critical regulator of PTPN1 (encoding PTP1B) transcription in human PCa cell lines and human PCa tissues. Importantly, we described PTP1B as a tumor promoter in these cell lines, particularly when the AR signaling axis was activated. Second, we described the frequent amplification of a chromosomal region within the hereditary PCa genetic-susceptibility locus located on chromosome 20 (HPC20) in metastatic tumors. Interestingly, PTPN1 is included in the maximal common amplified region, which is frequently co-amplified with the AR. This coordinated copy number gain might result in a synergistic increase in the transcription of most genes located on the amplicon as many are AR-regulated. Finally, using prostate-specific PTEN-null mice, we demonstrated that genetic depletion of PTPN1 results in a slightly more aggressive phenotype when mice are fed a regular chow diet. Strikingly, when mice are fed a high fat diet, PTPN1 knockout mice exhibited a dramatic increase in the number of microinvasive lesions that then progress to fully invasive carcinoma. In summary, the data presented herein identifies PTPN1 as a context-dependent PCa gene that can act as an oncogene when the AR signaling axis is activated, or as a tumor suppressor in PTEN-null tumors. These results suggest that parameters such as genetic alterations and diet should be taken into consideration when designing new clinical trials for PTP1B inhibitors in cancer." --