title: SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer.
abstract: The NAD-dependent histone deacetylase silent information regulator 1 (SIRT1) is overexpressed and catalytically activated in a number of human cancers, but recent studies have actually suggested that it may function as a tumor suppressor and metastasis inhibitor in vivo. In breast cancer, SIRT1 stabilization has been suggested to contribute to the oncogenic potential of the estrogen receptor α (ERα), but SIRT1 activity has also been associated with ERα deacetylation and inactivation. In this study, we show that SIRT1 is critical for estrogen to promote breast cancer. ERα physically interacted and functionally cooperated with SIRT1 in breast cancer cells. ERα also bound to the promoter for SIRT1 and increased its transcription. SIRT1 expression induced by ERα was sufficient to activate antioxidant and prosurvival genes in breast cancer cells, such as catalase and glutathione peroxidase, and to inactivate tumor suppressor genes such as cyclin G2 (CCNG2) and p53. Moreover, SIRT1 inactivation eliminated estrogen/ERα-induced cell growth and tumor development, triggering apoptosis. Taken together, these results indicated that SIRT1 is required for estrogen-induced breast cancer growth. Our findings imply that the combination of SIRT1 inhibitors and antiestrogen compounds may offer more effective treatment strategies for breast cancer.
authors.affiliation: Department of Biochemistry, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia, USA.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Elangovan
authors.forename: Sabarish
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Narayanan
authors.initials: N
authors.lastname: Venkatesan
authors.forename: Sudha
authors.initials: S
authors.lastname: Ananth
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gnana-Prakasam
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
authors.forename: Darren D
authors.initials: DD
authors.lastname: Browning
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Schoenlein
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
mesh_terms: D000107:Acetylation; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D015227:Lipid Peroxidation; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000737:chemistry / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009363:Neoplasm Proteins; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C447939:SIRT1 protein, human; D056564:Sirtuin 1