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.
©2011 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetylation
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Animals
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Antineoplastic Agents, Hormonal / pharmacology
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Antineoplastic Agents, Hormonal / therapeutic use
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Apoptosis / physiology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Breast Neoplasms / physiopathology*
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Cells, Cultured
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Epithelial Cells / metabolism
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Estrogen Receptor Modulators / pharmacology
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Estrogen Receptor Modulators / therapeutic use
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Estrogen Receptor alpha / chemistry
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Estrogen Receptor alpha / physiology*
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Estrogens / physiology*
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Female
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Gene Expression Regulation, Neoplastic
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Glutathione Peroxidase / biosynthesis
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Glutathione Peroxidase / genetics
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Humans
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Lipid Peroxidation
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Mice
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Mice, Nude
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasms, Hormone-Dependent / drug therapy
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Neoplasms, Hormone-Dependent / genetics
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Neoplasms, Hormone-Dependent / pathology
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Neoplasms, Hormone-Dependent / physiopathology*
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Protein Interaction Mapping
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Protein Processing, Post-Translational
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Signal Transduction / physiology*
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Sirtuin 1 / chemistry
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Sirtuin 1 / physiology*
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Specific Pathogen-Free Organisms
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Superoxide Dismutase / biosynthesis
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Superoxide Dismutase / genetics
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Tumor Stem Cell Assay
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Hormonal
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ESR1 protein, human
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Estrogen Receptor Modulators
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Estrogen Receptor alpha
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Estrogens
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Neoplasm Proteins
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Glutathione Peroxidase
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Superoxide Dismutase
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SIRT1 protein, human
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Sirtuin 1