PARP-1 as a potential therapeutic target in ERa-positive endocrine therapy-resistant breast cancer

Abstract Several endocrine therapy (ET) resistance mechanisms for ER-positive (ER+) breast cancer (BC) have been proposed, including acquired ESR1 (ERa gene) mutations. The two most common ESR1 mutations are Y537S and D538G, which give rise to a constitutively active receptor with reduced affinity for agonists and antagonists. The discovery of new effective therapies remains a significant challenge in treating mutated ER+ BC. In this context, Poly (ADP-ribose) polymerase-1 (PARP-1) has captured considerable interest as a target for therapeutic inhibitors in specific types of cancers. Here, we report that crosstalk between PARP-1 and ERa may represent a novel therapeutic approach for ER+ BC. We have demonstrated that the up-regulation of PARP-1 expression, stimulated by 17-ß estradiol (E2), was blocked by treatment with fulvestrant (Ful), a potent ERa antagonist, or ESR1 siRNA in ER+ MCF7 and T47D BC cell models that express both wild type ERa and the Y537S mutation, indicating that ERa regulates the expression of PARP-1. In addition, ERa-mediated transcriptional activity depended on PARP-1 activity in these models, as confirmed by ERa target gene expression and ERE reporter gene analyses +/- niraparib (Nira). Notably, PARP-1 modulates the estrogen-dependent genomic binding of ERa and FoxA1, which play a crucial role in the proliferation of ER+ BC. We also showed that PARP-1 inhibition prevented proliferation and cell cycle activities of ERa WT and ERa Y537S cells upon ERa activation. In vivo, Nira and lasofoxifene (Laso), an ERa antagonist, significantly reduced primary tumor growth versus vehicle, both as single agents and in combination. Moreover, RNA-seq analyses demonstrated the downregulation of ERa signaling in the mammary glands of mice treated with Nira versus Vehicle. Our results provide novel insights into the molecular events through which PARP-1 may serve as a more comprehensive therapeutic approach to target ET BC resistance in women with advanced ER+ BC. Overall design: Identification of transcriptomic profile, by RNA-seq, in the mammary glands of mice injected with ER-positive breast cancer cell lines MCF7, expressing heterozygous ERa Y537S mutations. The mice were treated with either the PARP-1 inhibitor, Niraparib, or with the selective estrogen-receptor modulator, Lasofoxifene as a single treatment or in combination. The objective is to gain new insights into individualized specific treatments for these specific malignancies.