Investigating the cooperative role of PARP1 and PRC2 in modulation of breast tumor microenvironment

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) and polycomb repressive complex 2 (PRC2) are each known for theirindividual roles in cancers, but their cooperative roles have only been studied in the DNA damage repair processin the context of BRCA-mutant cancers. Thus, the cooperative roles independent of DNA damage repair thatPARP1 and PRC2 play in cancer remain largely unknown. Here, I show that PARP1 and PRC2 double depletionin BRCA-proficient triple-negative breast cancer (TNBC) leads to a synthetic viability independent of the DNAdamage repair process. Specifically, PARP1 and PRC2 double-depleted TNBC tumors show accelerated growthwhen compared with wild type or single-depleted tumors. I attribute this to modifications in the tumormicroenvironment (TME) induced by double-depleted breast cancer cells changes like promoting intra-tumoralangiogenesis and increasing the proportion of tumor-promoting type 2 (M2) macrophages. These changessubsequently inhibit cell death and promote proliferation. Mechanistically, I find that PARP1 and PRC2 doubledepletion induces not only a basal activation of the NF-κB pathway but also a maximal activation of NF-κBwithin the TME in response to external stimuli such as hypoxia and the presence of macrophages. In summary,this study reveals an unprecedented synthetic viable interaction between PARP1 and PRC2 in BRCA-proficientTNBC and identifies NF-κB as the downstream mediator.