Abstract P2-05-08: Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin

Integrin α6β4 is highly expressed in triple negative breast cancer (TNBC) and drives aggressiveness by stimulating proliferation, angiogenesis, cell migration, invasion and metastasis. Signaling from this integrin stimulates DNA repair and apoptosis resistance, suggesting that it could contribute to therapeutic resistance. Upon testing this hypothesis, we found that integrin α6β4 signaling promoted a three-fold greater sensitivity to cisplatin but exhibited no difference in the response to other chemotherapies tested. Mechanistic investigations revealed that integrin α6β4 stimulated quicker and higher amplitude activations of ATM, Chk2, p53, and 53BP1, which required the 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 discovered that integrin α6β4 preferentially activated DNA-PKc in response to cisplatin, which led to formation of DNA-PKc-p53 complexes and 53BP1 activation. As a result, integrin α6β4 shifted double strand break repair from homologous recombination (HR) to non-homologous end joining (NHEJ), as demonstrated by HR and NHEJ reporter assays, in normal culture which was amplified by cisplatin treatment. Furthermore, DNA-PKc inhibition blocked integrin α6β4 enhanced cisplatin sensitivity. This signaling, against the backdrop of prominent losses and gains of select DNA repair molecules in breast cancer as a whole, may lead to a novel HR-deficiency that characterizes TNBC and their response to select chemotherapies. In summary, we discovered a novel function of integrin α6β4 in switching DSB repair from HR to NHEJ that results in cisplatin sensitivity in TNBC. Citation Format: Min Chen, Brock Marrs, Lei Qi, Teresa Knifley, Stuart G Jarrett, Heidi L Weiss, Rachel L Stewart, John A D9Orazio, Kathleen L O9Connor. Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-08.