Dicer-Mediated Upregulation of BCRP Confers Tamoxifen Resistance in Human Breast Cancer Cells
Menée in vitro et à l'aide de xénogreffes, cette étude identifie un mécanisme, lié à la surexpression de Dicer, permettant d'expliquer l'apparition d'une résistance au tamoxifène
Purpose: Tamoxifen (Tam) is the most prescribed hormonal agent for treatment of estrogen receptor alpha-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 ER alpha-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 ER alpha-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 5 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