title: 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 NFκB-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 NFκB in preexisting CSCs. Therefore, disruptions to the NFκB-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. Cancer Res; 76(7); 2000-12. ©2016 AACR.
authors: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors: Shilpi
authors: S
authors: Saha
authors: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors: Shravanti
authors: S
authors: Mukherjee
authors: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors: Poulami
authors: P
authors: Khan
authors: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors: Kirti
authors: K
authors: Kajal
authors: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors: Minakshi
authors: M
authors: Mazumdar
authors: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors: Argha
authors: A
authors: Manna
authors: Department of Physiology, Bankura Sammilani Medical College, Kenduadihi, Bankura, West Bengal, India.
authors: Sanhita
authors: S
authors: Mukherjee
authors: Department of Surgery, Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India.
authors: Sunanda
authors: S
authors: De
authors: Department of Surgery, Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India.
authors: Debarshi
authors: D
authors: Jana
authors: Department of Surgery, Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India.
authors: Diptendra K
authors: DK
authors: Sarkar
authors: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India. tanya@jcbose.ac.in.
authors: Tanya
authors: T
authors: Das
mesh_terms: D001241:Aspirin / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011446:Prospective Studies; D012189:Retrospective Studies; D014162:Transfection
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D001241:Aspirin