Abstract
Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described ‘regulator of regulators’ is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis.
Highlights
Breast cancer is a genetically heterogeneous disease that remains the most commonly diagnosed malignancy amongst women worldwide
We showed that the opposite functions of SIRT1 in breast cancer are closely related to the molecular subtype
We revealed that SIRT1 deficiency is associated with substantial induction of acetylated markers on six breast cancer-related gene promoters: androgen receptor (AR), BRCA1, ERS1, ERS2, EZH2, and EP300, suggesting an active role of SIRT1 in regulating the expression of these genes in Breast cancer (BC)
Summary
Breast cancer is a genetically heterogeneous disease that remains the most commonly diagnosed malignancy amongst women worldwide. Aberrant expression of HDACs in various human cancers, and their dysfunctional deacetylase activity, is deeply involved in the carcinogenesis process [3]. Due to its deacetylase activity, SIRT1 regulates a wide variety of fundamental cellular processes including apoptosis, DNA damage response and repair, cell differentiation and proliferation, chromatin remodeling and gene expression, endocrine signaling, aging, metabolism, stress response, and cancer development and metastasis [4,5,8,9,10]. Bifurcated SIRT1 can act as either a tumor suppressor or promoter in cancer cells This highly context-specific role of SIRT1 in breast carcinoma seems to depend mainly on its upstream regulators or downstream substrates, as well as on its spatial distribution, cellular and molecular context, and tumor types. We explore the mechanisms underlying SIRT1 opposite functions in breast carcinogenesis
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