PARP inhibitors (PARPi) are increasingly used in breast cancer therapy, including
high-grade triplenegative breast cancer (TNBC) treatment. Varying treatment responses
and PARPi resistance with relapse currently limit the efficacy of PARPi therapy. The
pathobiological reasons why individual patients respond differently to PARPi are poorly
understood. In this study, we analyzed the expression of PARP1, the main target of
PARPi, in normal breast tissue, breast cancer, and its precursor lesions using human
breast cancer tissue microarrays covering a total of 824 patients, including more
than 100 TNBC cases. In parallel, we analyzed nuclear adenosine diphosphate (ADP)ribosylation
as a marker of PARP1 activity and TRIP12, an antagonist of PARPi-induced PARP1 trapping.
Although we found PARP1 expression generally increased in invasive breast cancer,
PARP1 protein levels and nuclear ADP-ribosylation were lower in higher tumor grade
and TNBC samples than non-TNBCs. Cancers with low levels of PARP1 and low levels of
nuclear ADP-ribosylation were associated with significantly reduced overall survival.
This effect was even more pronounced in cases with high levels of TRIP12. These results
indicate that PARP1-dependent DNA repair capacity may be compromised in aggressive
breast cancers, potentially fueling enhanced accumulation of mutations. Moreover,
the results revealed a subset of breast cancers with low PARP1, low nuclear ADP-ribosylation,
and high TRIP12 levels, which may compromise their response to PARPi, suggesting a
combination of markers for PARP1 abundance, enzymatic activity, and trapping capabilities
might aid patient stratification for PARPi therapy.(c) 2023 THE AUTHORS. Published
by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This
is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).
