Dataset Information

The role of PARP-1 in estrogen-dependent transcription [ChIP-seq]

ABSTRACT: Poly (ADP-ribose) polymerase-1 (PARP-1), a multifunctional chromatin-modulating protein, has gained considerable attention as a target for therapeutic inhibitors in breast cancers. Accumulating evidence suggests a pathological role for PARP-1 in breast cancer through its effects on the transcription of tumor-related genes. Here we report the role of PARP-1 in estrogen-dependent transcription in estrogen receptor alpha (ERα)-positive breast cancers. Global nuclear run-on and sequencing (GRO-seq) analyses suggest that PARP-1 controls the expression of estrogen-regulated genes in ER-positive (ER+) MCF-7 breast cancer cells. Further, ChIP-seq analyses revealed that PARP-1 directly regulates the ligand-dependent binding of ERa and FoxA1 to a subset of its genomic binding sites. Finally, we uncovered that the expression levels of the PARP-1 and estrogen coregulated gene set are enriched in luminal molecular-subtype of breast tumors and high PARP-1 expression in ER+ cases correlates with poor survival. Additionally, treatment with PARP-1 selective inhibitors showed attenuated estrogen-dependent growth of ER+ breast cancer cells. Taken together, the current study suggests that PARP-1 regulates critical molecular pathways that underlie proliferation of ER+ breast cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166168 | GEO | 2021/10/13

REPOSITORIES: GEO

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Project description:Estrogen receptor positive breast cancer is the most prevalent form of breast cancer. Although a number of available drugs are highly effective at blocking estrogen mediated receptor activity, thousands of patients die every year from ER positive breast cancers because the disease progresses to a stage at which these drugs are no longer effective. Thus, it is crucial to establish a comprehensive understanding of the biology of the estrogen receptor (ER) in ER:positive breast cancers that progress despite hormone therapy, a gap in knowledge that remains a serious impediment to successful treatment of patients with ER positive breast cancer. A key question that must be answered is how the estrogen receptor retains the capacity to activate transcription in the absence or near absence of estrogen. We have found a partial answer to this question upon investigating the effect of amplification and overexpression of Wolf Hirschhorn Syndrome Candidate 1:Like 1 (WHSC1L1), a gene that is amplified in 15% of breast cancers that codes for a histone:lysine methyltransferase. WHSC1L1 lies in the 8p11:p12 amplicon, a region of gene amplification that is strongly associated with breast cancer. In this study, we performed shRNA knockdown of the catalytically inactive short isoform of WHSC1L1 in SUM44PE breast cancer cells and found that expression of the short isoform of WHSC1L1 is necessary for expression of the estrogen receptor in this highly ER:positive cell line. In addition, we found that the estrogen receptor binds chromatin extensively in the absence of exogenous estrogen, including several actively transcribed canonical ER target genes, indicating that estrogen receptor signaling is active in SUM44 cells in estrogen free conditions. These findings represent a novel model for ER biology in luminal B breast cancers harboring amplification of WHSC1L1 and provide insight into the mechanisms by which ER: positive breast cancers become unresponsive to SERMs or aromatase inhibitors.