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A Functional Genomi...
A Functional Genomic Screen Identifies the Deubiquitinase USP11 as a Novel Transcriptional Regulator of ERα in Breast Cancer
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- Dwane, Lisa (författare)
- Royal College of Surgeons in Ireland
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- O'Connor, Aisling E (författare)
- University College Dublin
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- Das, Sudipto (författare)
- Royal College of Surgeons in Ireland
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- Moran, Bruce (författare)
- University College Dublin
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- Mulrane, Laoighse (författare)
- University College Dublin
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- Pinto-Fernandez, Adan (författare)
- University of Oxford
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- Ward, Elspeth (författare)
- Royal College of Surgeons in Ireland
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- Blümel, Anna M (författare)
- Royal College of Surgeons in Ireland
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- Cavanagh, Brenton L (författare)
- Royal College of Surgeons in Ireland
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- Mooney, Brian (författare)
- Royal College of Surgeons in Ireland
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Dirac, Annette M (författare)
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- Jirström, Karin (författare)
- Lund University,Lunds universitet,Terapeutisk patologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Therapeutic pathology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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Kessler, Benedikt M (författare)
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Ní Chonghaile, Tríona (författare)
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Bernards, René (författare)
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Gallagher, William M (författare)
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O'Connor, Darran P (författare)
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(creator_code:org_t)
- 2020
- 2020
- Engelska.
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Ingår i: Cancer Research. - 1538-7445. ; 80:22, s. 5076-5088
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Approximately 70% of breast cancers express estrogen receptor α (ERα) and depend on this key transcriptional regulator for proliferation and differentiation. While patients with this disease can be treated with targeted antiendocrine agents, drug resistance remains a significant issue, with almost half of patients ultimately relapsing. Elucidating the mechanisms that control ERα function may further our understanding of breast carcinogenesis and reveal new therapeutic opportunities. Here, we investigated the role of deubiquitinases (DUB) in regulating ERα in breast cancer. An RNAi loss-of-function screen in breast cancer cells targeting all DUBs identified USP11 as a regulator of ERα transcriptional activity, which was further validated by assessment of direct transcriptional targets of ERα. USP11 expression was induced by estradiol, an effect that was blocked by tamoxifen and not observed in ERα-negative cells. Mass spectrometry revealed a significant change to the proteome and ubiquitinome in USP11-knockdown (KD) cells in the presence of estradiol. RNA sequencing in LCC1 USP11-KD cells revealed significant suppression of cell-cycle-associated and ERα target genes, phenotypes that were not observed in LCC9 USP11-KD, antiendocrine-resistant cells. In a breast cancer patient cohort coupled with in silico analysis of publicly available cohorts, high expression of USP11 was significantly associated with poor survival in ERα-positive (ERα+) patients. Overall, this study highlights a novel role for USP11 in the regulation of ERα activity, where USP11 may represent a prognostic marker in ERα+ breast cancer. SIGNIFICANCE: A newly identified role for USP11 in ERα transcriptional activity represents a novel mechanism of ERα regulation and a pathway to be exploited for the management of ER-positive breast cancer.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Breast Neoplasms/chemistry
- Cell Line, Tumor
- Deubiquitinating Enzymes/drug effects
- Estradiol/pharmacology
- Estrogen Antagonists/pharmacology
- Estrogen Receptor alpha/genetics
- Female
- Gene Silencing
- Genes, cdc
- Humans
- Phenotype
- Prognosis
- Proteome
- Tamoxifen/pharmacology
- Thiolester Hydrolases/drug effects
- Trans-Activators/physiology
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Dwane, Lisa
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O'Connor, Aislin ...
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Das, Sudipto
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Moran, Bruce
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Mulrane, Laoighs ...
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Pinto-Fernandez, ...
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visa fler...
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Ward, Elspeth
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Blümel, Anna M
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Cavanagh, Brento ...
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Mooney, Brian
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Dirac, Annette M
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Jirström, Karin
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Kessler, Benedik ...
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Ní Chonghaile, T ...
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Bernards, René
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Gallagher, Willi ...
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O'Connor, Darran ...
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
- Artiklar i publikationen
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Cancer Research
- Av lärosätet
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Lunds universitet