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PARP-1 Regulates Estrogen-Dependent Gene Expression in Estrogen Receptor α-Positive Breast Cancer Cells.

ABSTRACT: Poly(ADP-ribose) polymerase-1 (PARP-1) has gained considerable attention as a target for therapeutic inhibitors in breast cancers. Previously we showed that PARP-1 localizes to active gene promoters to regulate histone methylation and RNA polymerase II activity (Pol II), altering the expression of various tumor-related genes. Here we report a role for PARP-1 in estrogen-dependent transcription in estrogen receptor alpha (ERα)-positive (ER⁺) breast cancers. Global nuclear run-on and sequencing analyses functionally linked PARP-1 to the direct control of estrogen-regulated gene expression in ER⁺ MCF-7 breast cancer cells by promoting transcriptional elongation by Pol II. Furthermore, chromatin immunoprecipitation sequencing analyses revealed that PARP-1 regulates the estrogen-dependent binding of ERα and FoxA1 to a subset of genomic ERα binding sites, promoting active enhancer formation. Moreover, we found that the expression levels of the PARP-1- and estrogen-coregulated gene set are enriched in the luminal subtype of breast cancer, and high PARP-1 expression in ER⁺ cases correlates with poor survival. Finally, treatment with a PARP inhibitor or a transcriptional elongation inhibitor attenuated estrogen-dependent growth of multiple ER⁺ breast cancer cell lines. Taken together, our results show that PARP-1 regulates critical molecular pathways that control the estrogen-dependent gene expression program underlying the proliferation of ER⁺ breast cancer cells. IMPLICATIONS: PARP-1 regulates the estrogen-dependent genomic binding of ERα and FoxA1 to regulate critical gene expression programs by RNA Pol II that underlie the proliferation of ER⁺ breast cancers, providing a potential therapeutic opportunity for PARP inhibitors in estrogen-responsive breast cancers.

SUBMITTER: Gadad SS

PROVIDER: S-EPMC8492518 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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PARP-1 Regulates Estrogen-Dependent Gene Expression in Estrogen Receptor α-Positive Breast Cancer Cells.

Gadad Shrikanth S SS Camacho Cristel V CV Malladi Venkat V Hutti Charles R CR Nagari Anusha A Kraus W Lee WL

Molecular cancer research : MCR 20210622 10

Poly(ADP-ribose) polymerase-1 (PARP-1) has gained considerable attention as a target for therapeutic inhibitors in breast cancers. Previously we showed that PARP-1 localizes to active gene promoters to regulate histone methylation and RNA polymerase II activity (Pol II), altering the expression of various tumor-related genes. Here we report a role for PARP-1 in estrogen-dependent transcription in estrogen receptor alpha (ERα)-positive (ER<sup>+</sup>) breast cancers. Global nuclear run-on and se ...[more]

PMID: 34158394

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Project description:BackgroundEstrogens are known to regulate the proliferation of breast cancer cells and to modify their phenotypic properties. Identification of estrogen-regulated genes in human breast tumors is an essential step toward understanding the molecular mechanisms of estrogen action in cancer. To this end we generated and compared the Serial Analysis of Gene Expression (SAGE) profiles of 26 human breast carcinomas based on their estrogen receptor alpha (ER) status. Thus, producing a breast cancer SAGE database of almost 2.5 million tags, representing over 50,000 transcripts.ResultsWe identified 520 transcripts differentially expressed between ERalpha-positive (+) and ERalpha-negative (-) primary breast tumors (Fold change >or= 2; p < 0.05). Furthermore, we identified 220 high-affinity Estrogen Responsive Elements (EREs) distributed on the promoter regions of 163 out of the 473 up-modulated genes in ERalpha (+) breast tumors. In brief, we observed predominantly up-regulation of cell growth related genes, DNA binding and transcription factor activity related genes based on Gene Ontology (GO) biological functional annotation. GO terms over-representation analysis showed a statistically significant enrichment of various transcript families including: metal ion binding related transcripts (p = 0.011), calcium ion binding related transcripts (p = 0.033) and steroid hormone receptor activity related transcripts (p = 0.031). SAGE data associated with ERalpha status was compared with reported information from breast cancer DNA microarrays studies. A significant proportion of ERalpha associated gene expression changes was validated by this cross-platform comparison. However, our SAGE study also identified novel sets of genes as highly expressed in ERalpha (+) invasive breast tumors not previously reported. These observations were further validated in an independent set of human breast tumors by means of real time RT-PCR.ConclusionThe integration of the breast cancer comparative transcriptome analysis based on ERalpha status coupled to the genome-wide identification of high-affinity EREs and GO over-representation analysis, provide useful information for validation and discovery of signaling networks related to estrogen response in this malignancy.

Dataset Information

PARP-1 Regulates Estrogen-Dependent Gene Expression in Estrogen Receptor α-Positive Breast Cancer Cells.

Publications

PARP-1 Regulates Estrogen-Dependent Gene Expression in Estrogen Receptor α-Positive Breast Cancer Cells.

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