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bioRxiv · 10.1101/785873

Integrin α6β4 signaling switches DNA repair from homologous recombination to non-homologous end-joining pathway to sensitize breast cancer cells to cisplatin

Chen, M.·Marrs, B.·Qi, L.·Knifley, T.·Jarrett, S.·Weiss, H. L.·Stewart, R. L.·D'Orazio, J. A.·O'Connor, K. L.
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Abstract

Integrin 6{beta}4 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 6{beta}4 signaling promoted a three-fold greater sensitivity to cisplatin but exhibited no difference in response to other chemotherapies tested. Mechanistic investigations revealed that integrin 6{beta}4 stimulated quicker and higher amplitude of activation of ATM, Chk2, p53, and 53BP1, which required the integrin {beta}4 signaling domain. Genetic manipulation of gene expression demonstrated that mutant p53 cooperated with integrin 6{beta}4 for cisplatin sensitivity and was necessary for downstream phosphorylation of 53BP1 and enhanced ATM activation. Additionally, we discovered that integrin 6{beta}4 preferentially activated DNA-PKc in response to cisplatin, which led to formation of DNA-PKc-p53 complexes and 53BP1 activation. As a result, integrin 6{beta}4 shifted double strand break repair from homologous recombination (HR) to non-homologous end joining (NHEJ). In summary, we discovered a novel function of integrin 6{beta}4 in switching DSB repair from HR to NHEJ that results in cisplatin sensitivity in TNBC.

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Chen, M., Marrs, B., Qi, L., Knifley, T., Jarrett, S., Weiss, H. L., Stewart, R. L., D'Orazio, J. A., O'Connor, K. L.. 2019-09-30. Integrin α6β4 signaling switches DNA repair from homologous recombination to non-homologous end-joining pathway to sensitize breast cancer cells to cisplatin. https://doi.org/10.1101/785873

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