Abstract #5073

Background: Age is associated with increased incidence of cancer; therefore exploring factors associated with biological ageing in cancer may improve our understanding of the disease and result in new prognostic markers or therapeutic targets. Sirtuins belong to a family of genes that are involved in cell processes including DNA repair, cell-cycle regulation and ageing. SIRT6 modulates telomeric chromatin, is involved in DNA repair and the suppression of genomic instability, aberrations of which are key features of cancer cells. SIRT7 is a positive regulator of RNA polymerase I (Pol I) transcription. Recently, altered sirtuins expression has been linked with lung cancer, gliomas and thyroid cancer. This study aimed to investigate whether SIRT6 and SIRT7 expression is altered in breast tumour biopsies and to determine any association between sirtuin expression and patient outcome.
 Materials and Methods: The transcriptional expression of SIRT6 and SIRT7 was determined using real-time PCR in archival breast biopsies (73 non-malignant and 70 malignant). SIRT6 and SIRT7 expression relative to HPRT (house keeping gene) was then analysed with respect to histopathology, disease recurrence and survival.
 Results: We observed a significant decrease in the relative transcriptional expression of SIRT6 and SIRT7 in breast cancer biopsies (median for SIRT6 = 0.799 and SIRT7= 0.482) when compared with non-malignant tissue (median for SIRT6 = 1.823 and SIRT7= 0.607) (Mann-Whitney test, p <0.001 and p= 0.043 respectively). There was a significant association between SIRT6 expression and tumour grade (Kruskal Wallis Test, p=0.002), whereas only a trend was observed for SIRT7 (Kruskal Wallis Test, p=0.067). Kaplan-Meier survival analysis showed that mean survival was significantly shorter in patients with lower SIRT6 expression when compared with those with higher levels of expression (9.32 years vs 13.06 years, p=0.01). A trend was observed between levels of SIRT7 expression and survival (p=0.083). Furthermore, multivariate Cox-regression analysis revealed that SIRT6 expression was independent of tumour size, grade, nodal status, and oestrogen receptor status as a survival predictor (p =0.036).
 Discussion: These results demonstrate an association between SIRT6 expression and breast cancer pathogenesis and suggest possible SIRT7 involvement. Decreased SIRT6 expression is consistent with genomic instability associated with tumourigenesis and might indicated telomeric dysfunction. Lower levels of SIRT7 are an indication of increased biological ageing in cancerous cells. Furthermore, the association between SIRT6 and both tumour grade and survival, indicates that SIRT6 might prove to be an additional prognostic marker for breast cancer patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5073.

Thirty-first San Antonio Breast Cancer Symposium Dec 10-14, 2008; San Antonio, TX