Scientific Reports (Dec 2023)

SIRT6 promotes metastasis and relapse in HER2-positive breast cancer

  • Cristina Andreani,
  • Caterina Bartolacci,
  • Giuseppe Persico,
  • Francesca Casciaro,
  • Stefano Amatori,
  • Mirco Fanelli,
  • Marco Giorgio,
  • Mirco Galié,
  • Daniele Tomassoni,
  • Junbiao Wang,
  • Xiaoting Zhang,
  • Gregory Bick,
  • Roberto Coppari,
  • Cristina Marchini,
  • Augusto Amici

DOI
https://doi.org/10.1038/s41598-023-49199-7
Journal volume & issue
Vol. 13, no. 1
pp. 1 – 22

Abstract

Read online

Abstract The histone deacetylase sirtuin 6 (SIRT6) has been endowed with anti-cancer capabilities in many tumor types. Here, we investigate the impact of SIRT6-overexpression (SIRT6-OE) in Delta16HER2 mice, which are a bona fide model of HER2-positive breast cancer. After an initial delay in the tumor onset, SIRT6-OE induces a more aggressive phenotype of Delta16HER2 tumors promoting the formation of higher number of tumor foci and metastases than controls. This phenotype of SIRT6-OE tumors is associated with cancer stem cell (CSC)-like features and tumor dormancy, and low senescence and oxidative DNA damage. Accordingly, a sub-set of HER2-positive breast cancer patients with concurrent SIRT6-OE has a significant poorer relapse-free survival (RFS) probability than patients with low expression of SIRT6. ChIP-seq, RNA-seq and RT-PCR experiments indicate that SIRT6-OE represses the expression of the T-box transcription factor 3 (Tbx3) by deacetylation of H3K9ac. Accordingly, loss-of-function mutations of TBX3 or low TBX3 expression levels are predictive of poor prognosis in HER2-positive breast cancer patients. Our work indicates that high levels of SIRT6 are indicative of poor prognosis and high risk of metastasis in HER2-positive breast cancer and suggests further investigation of TBX3 as a downstream target of SIRT6 and co-marker of poor-prognosis. Our results point to a breast cancer subtype-specific effect of SIRT6 and warrant future studies dissecting the mechanisms of SIRT6 regulation in different breast cancer subtypes.