Evaluating the Role of Sirtuins 5, 6 & 7 in Breast Cancer.

Abstract

Abstract As cancer is a disease of ageing, genes involved in biological ageing may be informative in investigating the mechanisms of cancer pathogenesis. One such group of genes are the Sirtuins (SIRT1-7), orthologues of the yeast SIR2 gene, which are involved in cell processes including DNA repair, cell-cycle regulation and ageing. A definitive SIRT5 function is as yet unconfirmed, SIRT6 plays a role in DNA repair and suppression of genomic instability, whilst SIRT7 promotes ribosome biogenesis. Recently, altered sirtuin gene expression has been linked with a variety of cancers including breast. This study aimed to explore the role of SIRT5, 6 and 7 protein expression as predictive/prognostic markers in breast cancer patients.392 oestrogen receptor positive breast tumours were analysed for SIRT 5, 6 & 7 protein expression using an immunohistochemical approach. Prospective follow-up data was available for these patients; all patients received tamoxifen for a median of 5 years. Two observers independently scored the staining using a weighted histoscore method. Statistical analysis was carried out using the SPSS statistical program. For survival analysis, patients were split into two groups those that expressed high levels of the protein and those that expressed low levels. High levels were defined as IHC scores equal to or greater than the median value, whilst low levels were defined as scores less than the median value.Analysis of SIRT5 and SIRT7 expression yielded no significant associations with any clinical parameter investigated. SIRT6 protein expression did not affect overall survival for the 392 patients. However, it was observed that the mean time to relapse which occurred 5 years post diagnosis was significantly shorter in those patients with low SIRT6 expression compared to those with high SIRT6 expression (13.41yrs vs 15.84yrs p=0.032). Patients with low SIRT6 had a 2.26 times greater risk of relapse after 5 years than those with high SIRT6 expression (p=0.038). Furthermore when analysis of recurrence, which occurred 5 years post diagnosis, was stratified by progesterone receptor (PR) status, it was observed that SIRT6 failed to influence time to relapse in patients who were PR negative. However PR positive patients with low nuclear SIRT6 expression experienced a shorter mean time to recurrence compared to those with higher nuclear SIRT6 expression (13.88yrs vs 16.90yrs, p=0.045). PR positive patients with low SIRT6 expression had a similar mean time to recurrence, as those who were PR negative and had low SIRT6 expression.Current 5 year survival rates for breast cancer are approximately 80% however, it is well established that risk of recurrence persists after 5 years, these results indicate that low SIRT6 protein levels are associated with decreased time to relapse 5 years post diagnosis. This may be due to the fact that these patients are unable to maintain genomic integrity due to the role SIRT6 plays in BER. Furthermore low SIRT6 expression overrides the beneficial effects of PR positivity suggesting maintenance of genomic stability is more important than PR status in terms of recurrence. This study suggests that SIRT6 possibly represents a novel prognostic marker; furthermore it may identify patients who require additional therapies following tamoxifen treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3034.