Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

Abstract

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.

VEGF-A/Neuropilin 1 Pathway Confers Cancer Stemness via Activating Wnt/β-Catenin Axis in Breast Cancer Cells

“…The important mechanism contributing to chemoresistance is the high expression of ABC transporters in CSCs, like p-gp and MRP2 [16]. Moreover, CSCs seem preferentially increase their ability to repair DNA in response to drugs-induced DNA damage [17], again highlighting the potential of prohibiting CSCs formation to block cancer progression.…”

IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition

“…An inflammatory microenvironment has been shown to favor the maintenance of the breast TICs and their invasive behavior (17,18). However, insufficient data are available on the mechanisms regulating this phenomenon.…”

Cutaneous metastases of breast cancer during adjuvant chemotherapy correlates with increasing CD44+/CD24− and ALDH-1 expression: a case report and literature review

“…However, the latter study (19) also reported that patients with tumors containing high numbers of CD44 + /CD24 − cells more frequently developed bone metastases in the course of the disease. The molecular mechanisms underlying the roles of breast CSCs in chemoresistance have been reported in several studies (20,21) and proposed clinical implication for breast cancer therapeutics (22)(23)(24)(25). The occurrence of a fraction of breast CSCs with increased multidrug resistance (MDR) affinity clinically may be an additional mechanism for the positive selection of breast CSCs during chemotherapy (20).…”