Expression of E6AP and PML predicts for prostate cancer progression and cancer-specific death
BACKGROUND: The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of human tumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relationship and clinical impact of PML and E6AP expression in prostatic carcinoma is unknown. METHODS: E6AP and PML expression was assessed in tissue microarrays from a phase I discovery cohort of 170 patients treated by radical prostatectomy for localized prostate cancer (PC). Correlation analysis was carried out between PML and E6AP expression and clinicopathological variates including PSA as a surrogate of disease recurrence. The results were confirmed in a phase II validation cohort of 318 patients with associated clinical recurrence and survival data. RESULTS: Survival analysis of the phase I cohort revealed that patients whose tumors showed reduced PML and high E6AP expression had reduced time to PSA relapse (P = 0.012). This was confirmed in the phase II validation cohort where the expression profile of high E6AP/low PML was significantly associated with reduced time to PSA relapse (P < 0.001), clinical relapse (P = 0.016) and PC-specific death (P = 0.014). In multivariate analysis, this expression profile was an independent prognostic indicator of PSA relapse and clinical relapse independent of clinicopathologic factors predicting recurrence. CONCLUSION: This study identifies E6AP and PML as potential prognostic markers in localized prostate carcinoma and supports a role for E6AP in driving the downregulation or loss of PML expression in prostate carcinomas.
|ISBN||1569-8041 (Electronic) 0923-7534 (Linking)|
|Authors||Birch, S. E.; Kench, J. G.; Takano, E.; Chan, P.; Chan, A. L.; Chiam, K.; Veillard, A. S.; Stricker, P.; Haupt, S.; Haupt, Y.; Horvath, L.; Fox, S. B.;|
|Publisher Name||ANNALS OF ONCOLOGY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25231954|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12559|