Document Detail


The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer.
MedLine Citation:
PMID:  22878889     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aromatase inhibitors (AIs) are an effective therapy in treating estrogen receptor-positive breast cancer. Nonetheless, a significant percentage of patients either do not respond or become resistant to AIs. Decreased dependence on ER-signaling and increased dependence on growth factor receptor signaling pathways, particularly human epidermal growth factor receptor 2 (EGFR2/HER2), have been implicated in AI resistance. However, the role of growth factor signaling remains unclear. This current study investigates the possibility that signaling either through HER2 alone or through interplay between epidermal growth factor receptor 1 (EGFR/HER1) and HER2 mediates AI resistance by increasing the tumor initiating cell (TIC) subpopulation in AI-resistant cells via regulation of stem cell markers, such as breast cancer resistance protein (BCRP). TICs and BCRP are both known to be involved in drug resistance. Results from in vitro analyses of AI-resistant versus AI-sensitive cells and HER2-versus HER2+ cells, as well as from in vivo xenograft tumors, indicate that (1) AI-resistant cells overexpress both HER2 and BCRP and exhibit increased TIC characteristics compared to AI-sensitive cells; (2) inhibition of HER2 and/or BCRP decrease TIC characteristics in letrozole-resistant cells; and (3) HER2 and its dimerization partner EGFR/HER1 are involved in the regulation of BCRP. Overall, these results suggest that reducing or eliminating the TIC subpopulation with agents that target BCRP, HER2, EGFR/HER1, and/or their downstream kinase pathways could be effective in preventing and/or treating acquired AI resistance.
Authors:
Rabia A Gilani; Armina A Kazi; Preeti Shah; Amanda J Schech; Saranya Chumsri; Gauri Sabnis; Anil K Jaiswal; Angela H Brodie
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-10
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  135     ISSN:  1573-7217     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-12     Completed Date:  2013-04-19     Revised Date:  2013-08-19    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  681-92     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Experiment Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / metabolism
Animals
Aromatase Inhibitors / pharmacology*,  therapeutic use
Breast Neoplasms / drug therapy*,  metabolism,  pathology*
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Humans
MCF-7 Cells
Mice
Mice, Nude
Neoplasm Proteins / metabolism
Neoplastic Stem Cells / drug effects,  metabolism*,  pathology
Nitriles / pharmacology*
Receptor, Epidermal Growth Factor / metabolism
Receptor, erbB-2 / metabolism*
Signal Transduction / drug effects
Triazoles / pharmacology*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
R01 CA 62483/CA/NCI NIH HHS; R01 CA062483/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/ABCG2 protein, human; 0/Aromatase Inhibitors; 0/Neoplasm Proteins; 0/Nitriles; 0/Triazoles; 112809-51-5/letrozole; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/Receptor, erbB-2

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


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