|Title||Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells. |
|Publication Type||Journal Article |
|Year of Publication||2011 |
|Authors||Selever, Jennifer, Gu Guowei, Lewis Michael T., Beyer Amanda, Herynk Matthew H., Covington Kyle R., Tsimelzon Anna, Dontu Gabriela, Provost Patrick, Di Pietro Attilio, Boumendjel Ahcène, Albain Kathy, Miele Lucio, Weiss Heidi, Barone Ines, Ando Sebastiano, and Fuqua Suzanne A. W. |
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research |
|Date Published||2011 Oct 15 |
|Keywords||Animals, Antineoplastic Agents, Hormonal, 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. |
|Alternate Journal||Clin. Cancer Res. |