Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

ABSTRACT: Exploring epigenetic gene essentiality identifying key regulators of cell survival represents a promising way to exploit new targets to overcome resistance to current pharmacological regimens. In breast cancer (BC), endocrine therapy (ET) resistance arises from aberrant Estrogen Receptor alpha (ERα) signaling and targeting cancer cell vulnerability within the ERα pathway represents a rationale for development of effective new drugs against this disease. By combining bioinformatics analysis of genome-wide ‘drop-out’ screenings and siRNA-mediated gene knock-down (kd) we identified a set of essential genes that includes, as the most effective, the bromodomain containing protein BRPF1. BRPF1 belongs to a family of epigenetic readers acting as chromatin remodelers to control gene transcription. To gather mechanistic insight into the role of this epienzyme in BC, we applied chromatin and transcriptome profiling, gene ablation and specific pharmacological inhibition followed by cellular and functional assays. Experimental evidences indicate that BRPF1 associates with ERa in MCF-7 cells chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through modulation of chromatin accessibility. This results in a widespread inhibition of ER-dependent hormonal signaling obtained by ERa gene silencing in AE-sensitive and -resistant BC cells and pre-clinical patient-derived models (PDO). The characterization of functional interplays between ERα and BRPF1 revealed a new master regulator of BC survival, providing a rationale for a BRPF1 targeted cancer diagnosis and highlighting a new therapeutic vulnerability for the treatment of these aggressive tumors.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Giorgio Giurato

PROVIDER: E-MTAB-13884 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Breast Cancer (BC) is one of the main causes of cancer-related death in women. The most widespread BC subtype (75%) is the hormone-dependent, characterized by high expression of Estrogen Receptor Alpha (ERa). ERa exerts its oncogenic activity through the interaction with different co-regulators, carrying out a direct control on gene transcription and thus being the target of specific anticancer therapies. Despite the efficiency of these drugs, 30% of patients develop de novo or acquired resistance mechanisms, caused by alternative mechanisms that bypass antiestrogenic effects determining the onset of relapse. In order to identify new and potentially drugable Era molecular partners, essential genes for BC progression in luminal cell lines assessed by CRISPR-cas assay were compared to ERa interactome, dropping our focus on the tyrosine-protein kinase BAZ1B. BAZ1B is an essential component of the WICH complex and plays a crucial role in chromatin remodelling acting also as transcription regulator. In order to characterize the functional role of BAZ1B in luminal BC, we first employed a TCGA analysis that showed higher expression of BAZ1B in luminal BC associated with a worst overall survival and progression free survival of patient affected by this disease. A transcriptome profiling after BAZ1B silencing was performed in MCF-7 cells, highlighting an impact of modulated genes in key BC pathways including the estrogen signalling. BAZ1B silencing showed also an effect on cell growth, inhibiting cell proliferation and increasing apoptosis activation mechanisms promoted by the loss of ERa protein expression coupled to a reduction of the receptor transactivation activity. Interesting, these effects were confirmed also in antiestrogen (Tamoxifen and Fulvestrant) resistant BC cell models that retain ERa expression, suggesting BAZ1B as a novel and potentially exploitable therapeutic target in the treatment of both hormone dependent and resistant mammary tumours.

Project description:Abstract Several endocrine therapy (ET) resistance mechanisms for ER-positive (ER+) breast cancer (BC) have been proposed, including acquired ESR1 (ERα 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 ERα may represent a novel therapeutic approach for ER+ BC. We have demonstrated that the up-regulation of PARP-1 expression, stimulated by 17-β estradiol (E2), was blocked by treatment with fulvestrant (Ful), a potent ERα antagonist, or ESR1 siRNA in ER+ MCF7 and T47D BC cell models that express both wild type ERα and the Y537S mutation, indicating that ERα regulates the expression of PARP-1. In addition, ERα-mediated transcriptional activity depended on PARP-1 activity in these models, as confirmed by ERα target gene expression and ERE reporter gene analyses +/- niraparib (Nira). Notably, PARP-1 modulates the estrogen-dependent genomic binding of ERα 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 ERα WT and ERα Y537S cells upon ERα activation. In vivo, Nira and lasofoxifene (Laso), an ERα antagonist, significantly reduced primary tumor growth versus vehicle, both as single agents and in combination. Moreover, RNA-seq analyses demonstrated the downregulation of ERα 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.

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Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

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