The miR-362-3p/BCLAF1 axis regulates cisplatin sensitivity and metastatic progression in triple-negative breast cancer
Liu, Z.; Wu, C.; Uyemura, M.; Sardella, B. R.; Aronson, E. K.; Ke, S.; Massicott, E. S.; Li, X.; Wang, L.; Karagkouni, D.; Kalavros, N.; Vlachos, I. S.; Batalini, F.; Bogsan, C. S.; Cheong, J. K.; Zhou, L.; Cheng, H.; Munson, P.; Mayer, E. L.; Garber, J. E.; Schnitt, S. J.; Tung, N. M.; Kasinski, A. L.; Frank, S. J.; Wulf, G. M.; Heng, Y. J.
Show abstract
Platinum-based chemotherapy remains a cornerstone of treatment for triple-negative breast cancer (TNBC), yet the molecular determinants governing platinum response remain poorly defined. By leveraging the randomized Phase II INFORM trial, which compared neoadjuvant cisplatin to anthracycline-based therapy in BRCA1/2-mutant breast cancer--we identified miR-362-3p as a specific regulator of cisplatin sensitivity. Higher plasma miR-362-3p expression was exclusively associated with favorable clinical outcome in the cisplatin arm, with no association observed in the AC arm, decoupling platinum-specific vulnerability from general chemotherapy response. We used gain- and loss-of-function TNBC models to establish that miR-362-3p functions as a potent sensitizer to cisplatin in vitro and in vivo. Integrated TCGA analysis and experimental validation identified BCLAF1, a key regulator of DNA damage response, as a direct repression target of miR-362-3p. We uncovered a novel role for the miR-362-3p/BCLAF1 axis in overcoming platinum resistance in TNBC.
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