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.
Show 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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