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Therapeutic rationa...
Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer
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- Li, Bo (författare)
- University College Dublin
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- Chonghaile, Triona Ni (författare)
- Royal College of Surgeons in Ireland
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- Fan, Yue (författare)
- University College Dublin
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- Madden, Stephen F. (författare)
- Royal College of Surgeons in Ireland
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- Klinger, Rut (författare)
- University College Dublin
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- O'Connor, Aisling E. (författare)
- University College Dublin
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- Walsh, Louise (författare)
- Royal College of Surgeons in Ireland
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- O'Hurley, Gillian (författare)
- OncoMark Ltd
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- Udupi, Girish Mallya (författare)
- OncoMark Ltd
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- Joseph, Jesuchristopher (författare)
- OncoMark Ltd
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- Tarrant, Finbarr (författare)
- University College Dublin
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- Conroy, Emer (författare)
- University College Dublin
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- Gaber, Alexander (författare)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Chin, Suet-Feung (författare)
- University of Cambridge
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- Bardwell, Helen A (författare)
- University of Cambridge
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- Provenzano, Elena (författare)
- University of Cambridge
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- Crown, John P. (författare)
- St Vincent's University Hospital
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- Dubois, Thierry (författare)
- Curie Institute, Paris
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- Linn, Sabine (författare)
- Netherlands Cancer Institute
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- Jirstrom, Karin (författare)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Caldas, Carlos (författare)
- University of Cambridge
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- O'Connor, Darran P. (författare)
- Royal College of Surgeons in Ireland
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- Gallagher, William M (författare)
- OncoMark Ltd,University College Dublin
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(creator_code:org_t)
- 2017
- 2017
- Engelska 12 s.
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Ingår i: Cancer Research. - 0008-5472. ; 77:14, s. 3834-3845
- 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
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- Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n ¼ 383) and the METABRIC TNBC dataset (n ¼ 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n ¼ 109) and the METABRIC TNBC cohort (n ¼ 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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Li, Bo
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Chonghaile, Trio ...
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Fan, Yue
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Madden, Stephen ...
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Klinger, Rut
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O'Connor, Aislin ...
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visa fler...
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Walsh, Louise
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O'Hurley, Gillia ...
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Udupi, Girish Ma ...
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Joseph, Jesuchri ...
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Tarrant, Finbarr
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Conroy, Emer
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Gaber, Alexander
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Chin, Suet-Feung
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Bardwell, Helen ...
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Provenzano, Elen ...
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Crown, John P.
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Dubois, Thierry
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Linn, Sabine
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Jirstrom, Karin
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Caldas, Carlos
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O'Connor, Darran ...
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Gallagher, Willi ...
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Cancer Research
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