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 (GRO-seq) 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, ChIP-seq 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 cancers, 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 polymerase II that underlie the proliferation of ERα-positive breast cancers, providing a potential therapeutic opportunity for PARP inhibitors in estrogen-responsive breast cancers.

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