NAD+ levels decline with age and in certain disease conditions. NAD+ precursors have been shown to stimulate NAD+ biosynthesis and ameliorate various age-associated diseases in mouse models. However, NAD+ metabolism is complicated in cancer and its role in triple-negative breast cancer (TNBC) remains elusive. Here, we show that NAD+ supplement suppresses tumor metastasis in a TNBC orthotopic patient-derived xenograft (PDX) model. Sirtuin1 lysine deacetylase (SIRT1) is required for the effects since SIRT1 knockdown blocks NAD+-suppressed tumor metastasis. Overexpression of SIRT1 effectively impairs the metastatic potential of TNBC. Importantly, the interaction between SIRT1 and p66Shc causes the deacetylation and functional inactivation of p66Shc, which inhibits epithelial-mesenchymal transition (EMT). Overall, we demonstrate that NAD+ supplementation executes its anti-tumor function via activating the SIRT1-p66Shc axis, which highlights the preventive and therapeutic potential of SIRT1 activators as effective interventions for TNBC.
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The RNA sequence data in the present study have been deposited in the NCBI Gene Expression Omnibus (GEO) public database with the accession number GSE220683. All data are available from the authors upon reasonable request.
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We thank all the staff members of Luo laboratory for their technical support and critical suggestions. This work was supported by the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 20181821569) and the Self-Topic Fund of Tsinghua University (No. 20191080585).
The authors declare no competing interests.
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Jiang, Y., Luo, Z., Gong, Y. et al. NAD+ supplementation limits triple-negative breast cancer metastasis via SIRT1-P66Shc signaling. Oncogene 42, 808–824 (2023). https://doi.org/10.1038/s41388-023-02592-y