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Dicer-Mediated Upregulation of BCRP Confers Tamoxifen Resistance in Human Breast Cancer Cells
- Publication Year :
- 2011
-
Abstract
- Purpose: Tamoxifen (Tam) is the most prescribed hormonal agent for treatment of estrogen receptor α (ERα)-positive breast cancer patients. Using microarray analysis, we observed that metastatic breast tumors resistant to Tam therapy had elevated levels of Dicer. Experimental Design: We overexpressed Dicer in ERα-positive MCF-7 human breast cancer cells and observed a concomitant increase in expression of the breast cancer resistance protein (BCRP). We thus hypothesized that Tam resistance associated with Dicer overexpression in ERα-positive breast cancer cells may involve BCRP. We analyzed BCRP function in Dicer-overexpressing cells using growth in soft agar and mammosphere formation and evaluated intracellular Tam efflux. Results: In the presence of Tam, Dicer-overexpressing cells formed resistant colonies in soft agar, and treatment with BCRP inhibitors restored Tam sensitivity. Tumor xenograft studies confirmed that Dicer-overexpressing cells were resistant to Tam in vivo. Tumors and distant metastases could be initiated with as few as five mammosphere cells from both vector and Dicer-overexpressing cells, indicating that the mammosphere assay selected for cells with enhanced tumor-initiating and metastatic capacity. Dicer-overexpressing cells with elevated levels of BCRP effluxed Tam more efficiently than control cells, and BCRP inhibitors were able to inhibit efflux. Conclusion: Dicer-overexpressing breast cancer cells enriched for cells with enhanced BCRP function. We hypothesize that it is this population which may be involved in the emergence of Tam-resistant growth. BCRP may be a novel clinical target to restore Tam sensitivity. Clin Cancer Res; 17(20); 6510–21. ©2011 AACR.
- Subjects :
- Ribonuclease III
Cancer Research
Neoplasms, Hormone-Dependent
Abcg2
Antineoplastic Agents, Hormonal
Population
Estrogen receptor
Mice, Nude
Breast Neoplasms
Pharmacology
Article
DEAD-box RNA Helicases
Mice
Breast cancer
Cell Line, Tumor
medicine
ATP Binding Cassette Transporter, Subfamily G, Member 2
Animals
Humans
education
education.field_of_study
biology
Estrogen Antagonists
Estrogen Receptor alpha
Cancer
medicine.disease
Neoplasm Proteins
Up-Regulation
Disease Models, Animal
Tamoxifen
Oncology
Drug Resistance, Neoplasm
Cancer cell
Cancer research
biology.protein
ATP-Binding Cassette Transporters
Female
medicine.drug
Dicer
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....06d06aa0968fff5fa53ba9e6a8b0d841