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Endocrinology. 2014 Sep;155(9):3251-61. doi: 10.1210/en.2014-1002. Epub 2014 Jun 27.

The SMRT coregulator enhances growth of estrogen receptor-α-positive breast cancer cells by promotion of cell cycle progression and inhibition of apoptosis.

Author information

1
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.

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.

PMID:
24971610
PMCID:
PMC4138560
DOI:
10.1210/en.2014-1002
[Indexed for MEDLINE]
Free PMC Article

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