Title | Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Selever, J, Gu, G, Lewis, MT, Beyer, A, Herynk, MH, Covington, KR, Tsimelzon, A, Dontu, G, Provost, P, Di Pietro, A, Boumendjel, A, Albain, K, Miele, L, Weiss, H, Barone, I, Andò, S, Fuqua, SAW |
Journal | Clin Cancer Res |
Volume | 17 |
Issue | 20 |
Pagination | 6510-21 |
Date Published | 2011 Oct 15 |
ISSN | 1557-3265 |
Keywords | Animals, Antineoplastic Agents, Hormonal, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters, Breast Neoplasms, Cell Line, Tumor, DEAD-box RNA Helicases, Disease Models, Animal, Drug Resistance, Neoplasm, Estrogen Antagonists, Estrogen Receptor alpha, Female, Humans, Mice, Mice, Nude, Neoplasm Proteins, Neoplasms, Hormone-Dependent, Ribonuclease III, Tamoxifen, Up-Regulation |
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. |
DOI | 10.1158/1078-0432.CCR-11-1403 |
Alternate Journal | Clin Cancer Res |
PubMed ID | 21878538 |
PubMed Central ID | PMC3281508 |
Grant List | P01 CA030195-19 / CA / NCI NIH HHS / United States P01 CA030195 / CA / NCI NIH HHS / United States P01 CA030195-23 / CA / NCI NIH HHS / United States P30 CA125123 / CA / NCI NIH HHS / United States R01 CA072038-15W1 / CA / NCI NIH HHS / United States R01 CA072038 / CA / NCI NIH HHS / United States P01 CA30195 / CA / NCI NIH HHS / United States R01 CA72038 / CA / NCI NIH HHS / United States |
Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells.
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