Integrin α6β4 is highly expressed in triple negative breast cancer (TNBC) and drives its most aggressive traits; however, its impact on chemotherapeutic efficacy remains untested. We found that integrin α6β4 signaling promoted sensitivity to cisplatin and carboplatin but not to other chemotherapies tested. Mechanistic investigations revealed that integrin α6β4 stimulated the activation of ATM, p53, and 53BP1, which required the integrin β4 signaling domain. Genetic manipulation of gene expression demonstrated that mutant p53 cooperated with integrin α6β4 for cisplatin sensitivity and was necessary for downstream phosphorylation of 53BP1 and enhanced ATM activation. Additionally, we found that in response to cisplatin-induced DNA double strand break (DSB), integrin α6β4 suppressed the homologous recombination (HR) activity and enhanced non-homologous end joining (NHEJ) repair activity. Finally, we discovered that integrin α6β4 preferentially activated DNA-PK, facilitated DNA-PK-p53 and p53-53BP1 complex formation in response to cisplatin and required DNA-PK to enhance ATM, 53BP1 and p53 activation as well as cisplatin sensitivity. In summary, we discovered a novel function of integrin α6β4 in promoting cisplatin sensitivity in TNBC through DNA damage response pathway.
|Journal||Frontiers in Oncology|
|State||Published - Nov 10 2022|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health through National Cancer Institute (R01 CA223164-01 to KO’C, R21CA178753 to KO’C, and R01CA131075 to JD’O); the University of Kentucky Center for Cancer and Metabolism (P20GM121327) for providing imaging services and pilot funding (no number, to MC); by a Markey Women Strong Award through the Markey Cancer Foundation (no number, KO’C); and by the University of Kentucky Markey Cancer Center’s Support Grant (P30CA177558) to provide pilot funding (no number, to MC) and to enable services from the Markey Cancer Center Biospecimen Procurement and Translational Pathology, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resource Facilities.
Copyright © 2022 Chen, Marrs, Qi, Knifley, Weiss, D’Orazio and O’Connor.
- cisplatin sensitivity
- homologous recombination
- integrin signaling
- mutant p53
- non-homologous end joining
- triple negative breast cancer
ASJC Scopus subject areas
- Cancer Research