PARP1 and PRC2 double deficiency promotes BRCA‐proficient breast cancer growth by modification of the tumor microenvironment

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) and polycomb-repressive complex 2 (PRC2) are each known for their individual roles in cancer, but their cooperative roles have only been studied in the DNA damage repair process in the context of BRCA-mutant cancers. Here, we show that simultaneous inhibition of PARP1 and PRC2 in the MDA-MB-231 BRCA-proficient triplenegative breast cancer (TNBC) cell line leads to a synthetic viability independent of the mechanisms of DNA damage repair. Specifically, we find that either genetic depletion or pharmacological inhibition of both PARP1 and PRC2 can accelerate tumor growth rate. We attribute this to modifications in the tumor microenvironment (TME) that are induced by double-depleted breast cancer cells, such as promoting intratumoral angiogenesis and increasing the proportion of tumor-promoting type 2 (M2) macrophages. These changes subsequently inhibit cell death and promote proliferation. Mechanistically, we find that PARP1 and PRC2 double depletion induces not only a basal activation of the NF-jB pathway but also a maximal activation of NF-jB within the TME in response to external stimuli such as hypoxia and the presence of macrophages. In summary, our study reveals an unprecedented synthetic viable interaction between PARP1 and PRC2 in BRCA-proficient TNBC and identifies NF-jB as the downstream mediator.Database RNA-seq data are available in the GEO databases under the accession GSE142769.

Comprehensive Analysis of Pyroptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Breast Cancer

“…The low PyroptosisScore group showed a more abundant immune cell infiltration pattern. The TME has been shown to contribute to the occurrence and development of BRCA ( 47 , 48 ). The study by Bin-Zhi Qian et al.…”

Efficacy of PARP inhibition combined with EZH2 inhibition depends on BRCA mutation status and microenvironment in breast cancer

“…The combination of a PARPi and an EZH2 inhibitor has been evaluated in vitro and in vivo in breast cancer and ovarian cancer cells with varying BRCA mutation status [11,14,19,20] and has been proposed for clinical trial investigation (ClinicalTrials.gov identifier NCT04355858). However, the effect of this combination on the tumor microenvironment has not been thoroughly investigated, and it is not clear whether the synthetic viability of PARPi and EZH2 inhibitor is limited to BRCA-proficient breast cancer patients.…”

“…Interestingly, the function of PARP1 in DNA damage repair was not the key determining factor in the BRCA-proficient tumor growth promoted by PARP1 and PRC2 double depletion. Yang et al further demonstrated that the PARP1 and PRC2 double-depleted tumor cells not only proliferated faster than single-depleted counterparts in intratumoral regions, but also activated NF-jB signaling that secreted cytokines and chemokines to induce angiogenesis and increase differentiation into tumor-promoting M2 macrophages [19]. On the basis of these publications, the PARPi and EZH2 inhibitor combination may only benefit patients bearing BRCA1-mutated tumor (Fig.…”

“…While the studies published by Yamaguchi et al and Rondinelli et al focused on the effect of a PARPi combined with EZH2 inhibition on BRCA-mutated cancer cells [11,18], Yang et al [19] reported that the tumor-promoting effect of PARP1 depletion combined with PRC2 depletion in BRCA-proficient breast cancer resulted from NF-jB signaling-induced angiogenesis and macrophage differentiation. The PARP1 and PRC2 double-depleted cell was generated by knockout of PARP1 and knockdown of PRC2 protein expression by small hairpin RNA targeting of either EZH2 or SUZ12 [19]. Interestingly, the function of PARP1 in DNA damage repair was not the key determining factor in the BRCA-proficient tumor growth promoted by PARP1 and PRC2 double depletion.…”

The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions

“…For example, the histone methyltransferase polycomb repressive complex 2 (PRC2) is often mutated in cancers [ 109 ]. Inhibition or knockout of PARP-1 on an inactive PRC2 background leads to NF-κB activation, increased angiogenesis, and macrophage polarization to the tumor-promoting M2 phenotype [ 110 ]. Furthermore, in immune-mediated inflammation, the immunomodulatory roles of PARPs (see below) should also be taken into account.…”