BETs abet Tam-R in ER-positive breast cancer

Alluri, Prasanna; Asangani, Irfan A.; Chinnaiyan, Arul M.

doi:10.1038/cr.2014.90

Cited by 12 publications

(15 citation statements)

References 11 publications

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“…Interestingly, the small molecule BET inhibitor JQ1, already in use for hematological cancer, can potently deplete the classical ER signaling pathway and, in combination with fulvestrant, can more completely abolish ER protein levels in tamoxifen-resistant preclinical models 80 . These findings highlight a potential therapeutic role for ER epigenetic regulators in dealing with endocrine resistance 81 .…”

Section: Underlying Mechanisms Of Altered Er Activity In Endocrine Rementioning

confidence: 78%

The changing role of ER in endocrine resistance

et al. 2015

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SUMMARY Estrogen receptor (ER) is expressed in approximately 70% of newly diagnosed breast tumors. Although endocrine therapy targeting ER is highly effective, intrinsic or acquired resistance is common, significantly jeopardizing treatment outcomes and minimizing overall survival. Even in presence of endocrine resistance, a continued role of ER signaling is suggested by several lines of clinical and preclinical evidence. Indeed, inhibition or down-regulation of ER reduces tumor growth in preclinical models of acquired endocrine resistance, and many patients with recurrent ER+ breast tumors progressing on one type of ER-targeted treatment still benefit from sequential endocrine treatments that target ER by a different mechanism. New insights into the nature and biology of ER have revealed several mechanisms sustaining altered ER signaling in endocrine-resistant tumors, including deregulated growth factor receptor signaling that results in ligand-independent ER activation, unbalanced ER co-regulator activity, and genomic alterations involving the ER gene ESR1. Therefore, biopsies of recurrent lesions are needed to assess the changes in epi/genomics and signaling landscape of ER and associated pathways in order to tailor therapies to effectively overcome endocrine resistance. In addition, more completely abolishing the levels and activity of ER and its co-activators, in combination with selected signal transduction inhibitors or agents blocking the upstream or downstream targets of the ER pathway, may provide a better therapeutic strategy in combating endocrine resistance.

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Section: Underlying Mechanisms Of Altered Er Activity In Endocrine Rementioning

confidence: 78%

The changing role of ER in endocrine resistance

et al. 2015

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“…AFF4 regulates ESR1 gene expression. Previously we reported that bromodomain-containing proteins, BRD3/4, regulate transcription of ESR1 16,17 . As reported in literature, the BRD4 protein activates transcription through recruiting the positive transcription elongation factor, P-TEFb, which is composed of two subunits, cyclin T1 and CDK9 18 .…”

Section: Resultsmentioning

confidence: 99%

Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha

et al. 2020

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As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level.

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“…As enhancers provide bidirectional transcriptional regulation, we cloned both the sense and antisense sequences of the enhancer (−142~+ 3,457) into pGL3-basic vectors and transfected these vectors into HEK 293 T and MCF-7 cells. 28,29 Hence, ChIP-qPCR was performed to evaluate the enrichment of ZMYND8 and BRD4 at the LOL locus in MCF-7 and ZR-75-1 cells. 2b).…”

Section: Lol Is Transcribed From the Genomic Locus Of An Enhancermentioning

confidence: 99%

“…[25][26][27] BRD4 also plays a key role in tamoxifen resistance. 28,29 Hence, ChIP-qPCR was performed to evaluate the enrichment of ZMYND8 and BRD4 at the LOL locus in MCF-7 and ZR-75-1 cells. Not surprisingly, significant enrichment of both enhancer markers was observed in both cell lines ( Fig.…”

Section: Lol Is Transcribed From the Genomic Locus Of An Enhancermentioning

confidence: 99%

Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance

Sun

Jiang

et al. 2019

Intl Journal of Cancer

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Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let‐7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF‐7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF‐7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer‐regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.

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BETs abet Tam-R in ER-positive breast cancer

Cited by 12 publications

References 11 publications

The changing role of ER in endocrine resistance

The changing role of ER in endocrine resistance

Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha

Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance

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