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Long noncoding RNAs have been implicated in many of the hallmarks of cancer. Herein, we found that the expression of lncRNA152 (lnc152; a.k.a. DRAIC), which we annotated previously, is highly upregulated in luminal breast cancer (LBC) and downregulated in triple-negative breast cancer (TNBC). Knockdown of lnc152 promotes cell migration and invasion in LBC cell lines. In contrast, ectopic expression of lnc152 inhibits growth, migration, invasion, and angiogenesis in TNBC cell lines. In mice, lnc152 inhibited the growth of TNBC cell xenografts, as well as metastasis of TNBC cells in an intracardiac injection model. Transcriptome analysis of the xenografts indicated that lnc152 downregulates genes controlling angiogenesis. Using pull down assays followed by LC/MS-MS, we identified RBM47, a known tumor suppressor in breast cancer, as a lnc152-interacting protein. The effects of lnc152 in TNBC cells are mediated, in part, by regulating the expression of RBM47. Collectively, our results demonstrate that lnc152 is an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC., Implications: This study identifies lncRNA152 as an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC by upregulating the expression of the tumor suppressor RBM47. As such, lncRNA152 may serve as a biomarker to track aggressiveness of breast cancer, as well as therapeutic target for treating TNBC., (©2022 American Association for Cancer Research.)

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., (©2021 American Association for Cancer Research.)

The bromodomain family member proteins (BRD; BET proteins) are key coregulators for estrogen receptor alpha (ERα)-mediated transcriptional enhancers. The use of BRD-selective inhibitors has gained much attention as a potential treatment for various solid tumors, including ER-positive breast cancers. However, the roles of individual BET family members have largely remained unexplored. Here, we describe the role of BRDs in estrogen (E2)-dependent gene expression in ERα-positive breast cancer cells. We observed that chemical inhibition of BET family proteins with JQ1 impairs E2-regulated gene expression and growth in breast cancer cells. In addition, RNAi-mediated depletion of each BET family member (BRDs 2, 3, and 4) revealed partially redundant roles at ERα enhancers and for target gene transcription. Furthermore, we found a unique role of BRD3 as a molecular sensor of total BET family protein levels and activity through compensatory control of its own protein levels. Finally, we observed that BRD3 is recruited to a subset of ERα-binding sites (ERBS) that are enriched for active enhancer features, located in clusters of ERBSs likely functioning as "super enhancers," and associated with highly E2-responsive genes. Collectively, our results illustrate a critical and specific role for BET family members in ERα-dependent gene transcription. IMPLICATIONS: BRD3 is recruited to and controls the activity of a subset ERα transcriptional enhancers, providing a therapeutic opportunity to target BRD3 with BET inhibitors in ERα-positive breast cancers., (©2019 American Association for Cancer Research.)