Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells.

TitleDicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells.
Publication TypeJournal Article
Year of Publication2011
AuthorsSelever, 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
JournalClin Cancer Res
Date Published2011 Oct 15
KeywordsAnimals, 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

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.

Alternate JournalClin. Cancer Res.
PubMed ID21878538
PubMed Central IDPMC3281508
Grant ListP01 CA030195-19 / CA / NCI NIH HHS / United States
R01 CA072038-15W1 / CA / NCI NIH HHS / United States
P01 CA030195 / CA / NCI NIH HHS / United States
P01 CA030195-23 / 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