Document Detail

AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies.
MedLine Citation:
PMID:  22706627     Owner:  NLM     Status:  MEDLINE    
Aromatase inhibitors (AI) are currently the first line therapy for estrogen receptor (ER)-positive postmenopausal women. De novo AI resistance is when a patient intrinsically does not respond to an AI therapy as well as other targeted endocrine therapy. To characterize this type of resistance and to examine potential therapies for treatment, we have generated two cell models for de novo resistance. These models derive from MCF-7 cells that stably overexpress aromatase and Akt (AKT-aro) or HER2 (HER2-aro). Evaluation of these cell lines revealed that the activities of aromatase and ER were inhibited by AI and ICI 187280 (ICI) treatment, respectively; however, cell growth was resistant to therapy. Proliferation in the presence of the pure anti-estrogen ICI, indicates that these cells do not require ER for cell growth and distinguishes these cells from the acquired AI resistant cells. We further determined that the HSP90 inhibitor 17-DMAG suppressed the growth of the AI-resistant cell lines studied. Our analysis revealed 17-DMAG-mediated decreased expression of growth promoting signaling proteins. It was found that de novo AI resistant AKT-aro and HER2-aro cells could not be resensitized to letrozole or ICI by treatment with 17-DMAG. In summary, we have generated two cell lines which display the characteristics of de novo AI resistance. Together, these data indicate the possibility that HSP90 inhibitors may be a viable therapy for endocrine therapy resistance although additional clinical evaluation is needed.
Cynthie Wong; Xin Wang; David Smith; Kaladhar Reddy; Shiuan Chen
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Publication Detail:
Type:  Journal Article; Meta-Analysis; Research Support, N.I.H., Extramural     Date:  2012-06-16
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  134     ISSN:  1573-7217     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-23     Completed Date:  2012-11-23     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  671-81     Citation Subset:  IM    
Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology*,  therapeutic use
Aromatase / metabolism*
Aromatase Inhibitors / pharmacology*,  therapeutic use
Benzoquinones / pharmacology
Breast Neoplasms / drug therapy*,  enzymology,  mortality
Cell Line, Tumor / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Disease-Free Survival
Drug Resistance, Neoplasm*
Drug Synergism
Estradiol / analogs & derivatives,  pharmacology
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Expression Regulation, Neoplastic
HSP90 Heat-Shock Proteins / antagonists & inhibitors
Lactams, Macrocyclic / pharmacology
Nitriles / pharmacology
Proto-Oncogene Proteins c-akt / metabolism*
Receptor, erbB-2 / metabolism*
Receptors, Estrogen / metabolism
Transcriptional Activation
Triazoles / pharmacology
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Aromatase Inhibitors; 0/Benzoquinones; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; 0/Nitriles; 0/Receptors, Estrogen; 0/Triazoles; 001L2FE0M3/17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; 112809-51-5/letrozole; 22X328QOC4/fulvestrant; 50-28-2/Estradiol; EC; EC protein, human; EC, erbB-2; EC Proteins c-akt; EC Signal-Regulated MAP Kinases

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