Acquired chemoresistance has curtailed cancer survival since the dawn of chemotherapy. Accumulating evidence suggests a major role for cancer stem cells (CSC) in chemoresistance, although their involvement in acquired resistance is still unknown. The use of aspirin has been associated with reduced cancer risk and recurrence, suggesting that the anti-inflammatory drug may exert effects on CSCs. In this study, we investigated the contribution of CSCs to acquired chemoresistance of breast cancer and the avenues for reversing such effects with aspirin. We observed that the residual risk of recurrence was higher in breast cancer patients who had acquired chemoresistance. Treatment of preexisting CSCs with a genotoxic drug combination (5-fluorouracil, doxorubicin, and cyclophosphamide) generated an NFkB-IL6-dependent inflammatory environment that imparted stemness to nonstem cancer cells, induced multidrug resistance, and enhanced the migration potential of CSCs. Treatment with aspirin prior to chemotherapy suppressed the acquisition of chemoresistance by perturbing the nuclear translocation of NFkB in preexisting CSCs. Therefore, disruptions to the NFkB-IL6 feedback loop prevented CSC induction and sensitized preexisting CSCs to chemotherapy. Collectively, our findings suggest that combining aspirin and conventional chemotherapy may offer a new treatment strategy to improve recurrence-free survival of breast cancer patients.

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<p>Supplementary Figure S1: Immunohistological images representing ER, PR and Her2 staining of primary tumor cells and schematic representation showing flow cytometric sorting. Supplementary Figure S2: FAC-based chemotherapy increases CSC pool in different breast cancer cells. Supplementary Figure S3: FAC-based chemotherapy generates aggressive CSC pool. Supplementary Figure S4: Therapy fails to induce CSC-markers in purified NSCCs of MCF-7 cells. Supplementary Figure S5: Therapy induces translocation of NFκB in nucleus of CSCs. Supplementary Figure S6: Aspirin treatment perturbs NFκB nuclear translocation in CSC-enriched spheres and chemo-sensitizes CSCs to genotoxic therapy.</p>

<p>Supplementary Table IA: Pathological and clinical information of the chemotherapy-treated breast cancer patients included in the study. Supplementary Table IB: Pathological and clinical information of the untreated breast cancer patients included in the study. Supplementary Table II: List of primary and secondary antibodies used in the study, Primer sets for RT-PCR, Primer sets for ChIP.</p>