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

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 (ER alpha)-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 ER alpha and FoxA1 to a subset of genomic ER alpha 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 PARP1 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.

Automated summary

PARP-1 plays a crucial role in regulating estrogen-dependent gene expression in ER+ breast cancer cells, impacting cell proliferation. High expression of PARP1 is associated with poor prognosis, suggesting PARP inhibitors as a potential therapeutic approach for ER+ breast cancer.