title: The SMRT coregulator enhances growth of estrogen receptor-α-positive breast cancer cells by promotion of cell cycle progression and inhibition of apoptosis.
abstract: The SMRT coregulator functions as a dual coactivator and corepressor for estrogen receptor-α (ERα) in a gene-specific manner, and in several studies its elevated expression correlates with poor outcome for breast cancer patients. A specific role of SMRT in breast cancer progression has not been elucidated, but SMRT knock-down limits estradiol-dependent growth of MCF-7 breast cancer cells. In this study, small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) approaches were used to determine the effects of SMRT depletion on growth of ERα-positive MCF-7 and ZR-75-1 breast cancer cells, as well as the ERα-negative MDA-MB-231 breast cancer line. Depletion of SMRT inhibited growth of ERα-positive cells grown in monolayer but had no effect on growth of the ERα-negative cells. Reduced SMRT levels also negatively impacted the anchorage-independent growth of MCF-7 cells as assessed by soft agar colony formation assays. The observed growth inhibitions were due to a loss of estradiol-induced progression through the G1/S transition of the cell cycle and increased apoptosis in SMRT-depleted compared with control cells. Gene expression analyses indicated that SMRT inhibits apoptosis by a coordinated regulation of genes involved in apoptosis. Functioning as a dual coactivator for anti-apoptotic genes and corepressor for pro-apoptotic genes, SMRT can limit apoptosis. Together these data indicate that SMRT promotes breast cancer progression through multiple pathways leading to increased proliferation and decreased apoptosis.
authors: Molecular and Cellular Biology (J.K.B., S.K., V.C., C.L.S.), Lester and Sue Smith Breast Center (G.G.), and Dan L Duncan Cancer Center (L.W., W.L.), Baylor College of Medicine, Houston, Texas 77030.
authors: Julia K
authors: JK
authors: Blackmore
authors: Sudipan
authors: S
authors: Karmakar
authors: Guowei
authors: G
authors: Gu
authors: Vaishali
authors: V
authors: Chaubal
authors: Liguo
authors: L
authors: Wang
authors: Wei
authors: W
authors: Li
authors: Carolyn L
authors: CL
authors: Smith
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002453:Cell Cycle; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2