title: Identification of Sirtuin 3, a mitochondrial protein deacetylase, as a new contributor to tamoxifen resistance in breast cancer cells.
abstract: The current study reports a previously unappreciated role of Sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, in altering sensitivity of breast cancer cells to tamoxifen (Tam), a commonly used anti-estrogen agent. We showed that SIRT3 was significantly up-regulated at both mRNA and protein levels in the Tam-resistance human breast cancer cell line MTR-3, which was derived from MCF-7 line by continuous selective culture in the presence of 1μM of Tam for two years. We further demonstrated that SIRT3 was rapidly up-regulated in the sensitive MCF-7 cells following exposure to Tam. Transfection of MCF-7 cells with a SIRT3 expression plasmid decreased cellular sensitivity to Tam and blocked the Tam-induced apoptosis. Furthermore, silencing of SIRT3 expression in MTR-3 cells sensitized the resistant cells to Tam and enhanced apoptotic cell death. MTR-3 cells with silencing of SIRT3 expression showed increases in the mitochondrial content of ERβ, ROS level and apoptosis. These results not only uncovered a new role for SIRT3 in cancer but also identified this mitochondrial protein deacetylase as a previously unrecognized factor that participates in regulation of Tam sensitivity in breast cancer cells. Thus, SIRT3 might be considered as a potential target for overcoming Tam resistance in treatment of breast cancer.
authors.affiliation: Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Xingcong
authors.initials: X
authors.lastname: Ren
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Kathryn
authors.initials: K
authors.lastname: Huber-Keener
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yun-Sheng
authors.initials: YS
authors.lastname: Yuan
authors.forename: Jay W
authors.initials: JW
authors.lastname: Yang
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047629:Estrogen Receptor beta; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013629:Tamoxifen; C466093:SIRT3 protein, human; D056566:Sirtuin 3
keywords: Breast cancer; Drug resistance; ERβ; SIRT3; Tamoxifen