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BET Inhibition as a...
BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
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- Walsh, Louise (author)
- Royal College of Surgeons in Ireland
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- Haley, Kathryn E (author)
- Royal College of Surgeons in Ireland
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- Moran, Bruce (author)
- University College Dublin
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- Mooney, Brian (author)
- Royal College of Surgeons in Ireland
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- Tarrant, Finbarr (author)
- University College Dublin
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- Madden, Stephen F (author)
- Royal College of Surgeons in Ireland
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- Di Grande, Alessandra (author)
- Royal College of Surgeons in Ireland
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- Fan, Yue (author)
- University College Dublin
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- Das, Sudipto (author)
- Royal College of Surgeons in Ireland
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- Rueda, Oscar M (author)
- University of Cambridge
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- Dowling, Catríona M (author)
- Royal College of Surgeons in Ireland
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Varešlija, Damir (author)
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Chin, Suet-Feung (author)
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Linn, Sabine (author)
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Young, Leonie S (author)
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- Jirström, Karin (author)
- Lund University,Lunds universitet,Personlig patologi och cancerbehandling,Forskargrupper vid Lunds universitet,Personalized Pathology & Cancer Therapy,Lund University Research Groups
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Crown, John P (author)
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Bernards, Rene (author)
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Caldas, Carlos (author)
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Gallagher, William M (author)
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O'Connor, Darran P (author)
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Ní Chonghaile, Tríona (author)
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(creator_code:org_t)
- 2019
- 2019
- English.
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In: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 25:23, s. 7139-7150
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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
Subject headings
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- PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC.EXPERIMENTAL DESIGN: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples.RESULTS: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC.CONCLUSIONS: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Aniline Compounds/pharmacology
- Antineoplastic Agents/pharmacology
- Apoptosis
- Azepines/pharmacology
- Breast Neoplasms/drug therapy
- Carcinoma, Lobular/drug therapy
- Cell Cycle
- Cell Proliferation
- Cohort Studies
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Neoplasm Invasiveness
- Prognosis
- Receptor, ErbB-2/metabolism
- Receptors, Estrogen/metabolism
- Receptors, Progesterone/metabolism
- Sulfonamides/pharmacology
- Survival Rate
- Transcription Factors/antagonists & inhibitors
- Triazoles/pharmacology
- Tumor Cells, Cultured
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Walsh, Louise
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Haley, Kathryn E
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Moran, Bruce
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Mooney, Brian
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Tarrant, Finbarr
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Madden, Stephen ...
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show more...
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Di Grande, Aless ...
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Fan, Yue
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Das, Sudipto
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Rueda, Oscar M
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Dowling, Catríon ...
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Varešlija, Damir
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Chin, Suet-Feung
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Linn, Sabine
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Young, Leonie S
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Jirström, Karin
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Crown, John P
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Bernards, Rene
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Caldas, Carlos
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Gallagher, Willi ...
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O'Connor, Darran ...
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Ní Chonghaile, T ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Clinical cancer ...
- By the university
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Lund University