The Role of SIRT2, SIRT3 and SIRT4 in Breast Cancer.

Abstract

Abstract Introduction: The Silent Information Regulator 2 (Sir2) gene family regulates lifespan in lower eukaryotes. In mammals, 7 SIR2 orthologues exist, SIRT(1 -7) and are involved in DNA repair, cell cycle regulation and ageing. It has been previously hypothesised that SIRT proteins may be involved in a number of age related diseases including cancers. This study aimed to determine the potential role of SIRT 2, 3 and 4 proteins as prognostic and predictive markers in breast cancer patients.Methods: 392 oestrogen receptor positive breast tumours were analysed for SIRT 2, 3 & 4 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 and 95 received chemotherapy. 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 of interest 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.Results: High SIRT2 expression was associated with positive nodal status (p=0.016) and NPI group 3 (p=0.008). There was no association with SIRT2 expression and patient outcome. Low SIRT3 expression was associated with grade 3 tumours (p = 0.043) and HER2 positivity (p=0.016). Survival analysis revealed no association between levels of SIRT3 and disease-free (DFS) or overall survival. Analysis was performed on a subgroup of patients who had not relapsed within the first 3 years. Patients with low levels of SIRT3 had shorter DFS after 3 years and were 1.8 times more likely to relapse than high expressors (p = 0.026). SIRT3 expression was independent of grade, nodes status and size in influencing outcome (p=0.02). Analysis of the 285 tamoxifen only treated patients revealed low SIRT3 expression was associated with a shorter DFS (p = 0.048, HR=1.56). When survival analysis was performed on the patients that received both Tamoxifen and chemotherapy, the survival advantage for those patients expressing high levels of SIRT3 was lost. No significant associations were observed between SIRT4 and known prognostic markers and patient outcome.Discussion: Currently SIRT3 is the only sirtuin that is directly linked to extended lifespan in humans, SIRT3 slows oxidative damage and the cellular aging process. Our study found that those tumours expressing low SIRT3 were the most aggressive, exhibiting higher grade and positive HER2 status. Possibly those patients who are low SIRT3 expressers have reduced protection against ROS-induced cellular damage and thus tumorigenesis. This study therefore supports previous findings that low SIRT3 expression permits oxidative damage and predisposes to cancer. Low levels of SIRT3 expression was associated with a poorer prognosis, independently of grade, nodes and size. This strengthens the argument that SIRT3 is a novel prognostic marker, and not simply a surrogate marker of one of the already known prognostic markers. Our data also suggests that SIRT3 has the potential to identify patients who require additional therapies such as chemotherapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3032.