Document Detail


Tamoxifen and ICI 182,780 increase Bcl-2 levels and inhibit growth of breast carcinoma cells by modulating PI3K/AKT, ERK and IGF-1R pathways independent of ERalpha.
MedLine Citation:
PMID:  19002577     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We recently showed that estrogen withdrawal from the ERalpha(+), high Bcl-2-expressing breast carcinoma cells (MCF-7B) reduced Bcl-2 protein levels while increasing cell-cell adhesion, and junction formation. Here we compared these cells with the ERalpha(+) and low Bcl-2-expressing MCF-7 cells and with the normal mammary epithelial cell line MCF-10-2A not expressing ERalpha or Bcl-2. All cell lines expressed normal HER2. Antiestrogen (Tamoxifen and ICI 182,780) treatment increased Bcl-2 levels in both MCF-7 and -7B cells and led to the formation of acinar structures. This treatment led to the dissociation of junctions and redistribution of junctional components to the cytoplasm in MCF-10-2A and -7 cells, while in MCF-7B cells junctional proteins redistributed to membranes. Antiestrogen treatment decreased PI3K/Akt activation and increased ERK activation regardless of ERalpha status. IGF-1R was inactivated in the antiestrogen-treated MCF-7 cells while it was activated in MCF-7B cells. Our data show that Tamoxifen and ICI 182,780 can induce growth inhibitory effects via the sustained activation/inactivation of signaling pathways that regulate cell survival, cell death and differentiation in the absence of ERalpha. Furthermore, Bcl-2 overexpression may alter the functional interactions among these pathways in response to antiestrogens, which also may provide a potential explanation for the observation that Bcl-2 overexpressing tumors have a better prognosis.
Authors:
Le Lam; Xiuying Hu; Zackie Aktary; David W Andrews; Manijeh Pasdar
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-11
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  118     ISSN:  1573-7217     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-11-10     Completed Date:  2010-01-22     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  605-21     Citation Subset:  IM    
Affiliation:
Department of Cell Biology, University of Alberta, 6-24 Medical Sciences Building, Edmonton, AB, Canada, T6G 2H7.
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MeSH Terms
Descriptor/Qualifier:
Blotting, Western
Breast Neoplasms / metabolism*
Cell Adhesion / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Connexins / drug effects
Estradiol / analogs & derivatives*,  pharmacology
Estrogen Receptor alpha / drug effects,  metabolism
Extracellular Signal-Regulated MAP Kinases / drug effects,  metabolism
Female
Fluorescent Antibody Technique
Humans
Phosphatidylinositol 3-Kinases / drug effects,  metabolism
Proto-Oncogene Proteins c-akt / drug effects,  metabolism
Proto-Oncogene Proteins c-bcl-2 / drug effects*,  metabolism
Receptor, IGF Type 1 / drug effects,  metabolism
Selective Estrogen Receptor Modulators / pharmacology*
Signal Transduction / drug effects*
Tamoxifen / pharmacology*
Chemical
Reg. No./Substance:
0/Connexins; 0/Estrogen Receptor alpha; 0/Proto-Oncogene Proteins c-bcl-2; 0/Selective Estrogen Receptor Modulators; 10540-29-1/Tamoxifen; 22X328QOC4/fulvestrant; 50-28-2/Estradiol; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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