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bioRxiv · 10.1101/2021.05.14.444217

Mammary lineage dictates homologous recombination repair and PARP inhibitor vulnerability

Kim, H.·Casey, A. E.·Palomero, L.·Mahendralingam, M.·Parsons, M.·Narala, S.·Mateo, F.·Hofer, S.·Waterhouse, P. D.·Kislinger, T.·Pujana, M. A.·Berman, H. K.·Khokha, R.
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Abstract

It has long been assumed that all normal cells have the same capacity to engage homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DNA double-strand breaks (DSBs), a concept exploited for DNA-damaging chemotherapeutics. We show that mammary epithelial lineage dictates the DSB repair pathway choice. Primary mammary proteomes and DSB repair enumeration by {gamma}-H2AX, Rad51 and DNA-PKc foci reveal that NHEJ operates in all epithelial cells, but high-fidelity HR is restricted to the luminal lineage. This translates to divergent poly (ADP-ribose) polymerase inhibitor (PARPi) vulnerability of mammary epithelial progenitor activity in both mouse and human, irrespective of the BRCA1/2 status. Proteome-defined lineage-specific signatures correlate to breast cancer subtypes and predict PARPi response of triple-negative human breast cancer xenografts. These intrinsically divergent HR characteristics of mammary cell types underpin a new strategy for identifying PARPi responders.

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Kim, H., Casey, A. E., Palomero, L., Mahendralingam, M., Parsons, M., Narala, S., Mateo, F., Hofer, S., Waterhouse, P. D., Kislinger, T., Pujana, M. A., Berman, H. K., Khokha, R.. 2021-05-17. Mammary lineage dictates homologous recombination repair and PARP inhibitor vulnerability. https://doi.org/10.1101/2021.05.14.444217

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