Evidence map›Paper›PMID 39048045›Full record

ArticleCancer letters2025

The Megacomplex protects ER-alpha from degradation by Fulvestrant in epithelial ovarian cancer.

Sushil Kumar Jaiswal, Kevin Fedkenheuer, Ronak Khamar, Hua Tan, Valer Gotea, Sonam Raj, Michael Fedkenheuer, Abdel Elkahloun, Ming Zhao, Lisa M Jenkins and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Sushil Kumar JaiswalTranslational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Kevin FedkenheuerTranslational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Ronak KhamarTranslational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Hua TanTranslational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Valer GoteaTranslational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Sonam RajGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, 20892, USA.
Michael FedkenheuerMolecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Abdel ElkahlounMicroarrays and Single-Cell Genomics Core, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Ming ZhaoProteins and Chemistry Core, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, Rockville, MD, 20852, USA.
Lisa M JenkinsMass Spectrometry Resource, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA.
Christina M AnnunziataWomen's Malignancies Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Laura ElnitskiTranslational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, 20892, USA. Electronic address: elnitski@nih.gov.

Funding

Infectious Diseases Research Technologies Core - BethesdaZICAI001051 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI CHERRY, JAMES · 2009 to 2025
$226.1M
Regulatory and epigenetic landscapes reveal biological processes, disease mechanisms and diagnostic markersZIAHG200323 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI ELNITSKI, LAURA L · 2009 to 2025
$27.6M
Nuclear Factor-kappaB in Ovarian CancerZIABC011054 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI ANNUNZIATA, CHRISTINA · 2009 to 2023
$12.1M
Genomic-Functional Analyses-Conserved Noncoding RegionsZ01HG200323 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI ELNITSKI, LAURA L · 2005 to 2008
$2.3M
Intramural NIH HHS Z01 HG200323Intramural NIH HHS ZIA BC011054Intramural NIH HHS ZIA HG200323
6 · The paper itself

Abstract

Ovarian cancer, a significant contributor to cancer-related mortality, exhibits limited responsiveness to hormonal therapies targeting the estrogen receptor (ERα). This study aimed to elucidate the mechanisms behind ERα resistance to the therapeutic drug Fulvestrant (ICI182780 or ICI). Notably, compared to the cytoplasmic version, nuclear ERα was minimally degraded by ICI, suggesting a mechanism for drug resistance via the protective confines of the nuclear substructures. Of these substructures, we identified a 1.3 MDa Megacomplex comprising transcription factors ERα, FOXA1, and PITX1 using size exclusion chromatography (SEC) in the ovarian cancer cell line, PEO4. ChIP-seq revealed these factors colocalized at 6775 genomic positions representing sites of Megacomplex formation. Megacomplex ERα exhibited increased resistance to degradation by ICI compared to cytoplasmic and nuclear ERα. A small molecule inhibitor of active chromatin and super-enhancers, JQ1, in combination with ICI significantly enhanced ERα degradation from Megacomplex as revealed by SEC and ChIP-seq. Interestingly, this combination degraded both the cytoplasmic as well as nuclear ERα. Pathway enrichment analysis showed parallel results for RNA-seq gene sets following Estradiol, ICI, or ICI plus JQ1 treatments as those defined by Megacomplex binding identified through ChIP-seq. Furthermore, similar pathway enrichments were confirmed in mass-spec analysis of the Megacomplex macromolecule fractions after modulation by Estradiol or ICI. These findings implicate Megacomplex in ERα-driven ovarian cancer chromatin regulation. This combined treatment strategy exhibited superior inhibition of cell proliferation and viability. Therefore, by uncovering ERα's resistance within the Megacomplex, the combined ICI plus JQ1 treatment elucidates a novel drug treatment vulnerability.

Indexed as

Carcinoma, Ovarian EpithelialEstrogen Receptor alphaFulvestrantOvarian NeoplasmsAntineoplastic Agents, HormonalAzepinesCell Line, TumorDrug Resistance, NeoplasmFemaleHepatocyte Nuclear Factor 3-alphaHumansProteolysisTriazolesAntineoplastic Agents, HormonalAzepinesESR1 protein, humanEstrogen Receptor alphaFulvestrantHepatocyte Nuclear Factor 3-alpha(+)-JQ1 compoundTriazolesBRD4 inhibitorChIP-seqDrug resistanceEstrogen receptorGel filtrationICI182780JQ1MegacomplexOvarian cancerSuper-enhancer

Identifiers

PMID39048045
PMCPMC12276986

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.