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Translational Cancer Mechanisms and Therapy

BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer

Louise Walsh, Kathryn E. Haley, Bruce Moran, Brian Mooney, Finbarr Tarrant, Stephen F. Madden, Alessandra Di Grande, Yue Fan, Sudipto Das, Oscar M. Rueda, Catríona M. Dowling, Damir Varešlija, Suet-Feung Chin, Sabine Linn, Leonie S. Young, Karin Jirström, John P. Crown, Rene Bernards, Carlos Caldas, William M. Gallagher, Darran P. O'Connor and Tríona Ní Chonghaile
Louise Walsh
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Kathryn E. Haley
Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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  • ORCID record for Kathryn E. Haley
Bruce Moran
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
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Brian Mooney
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Finbarr Tarrant
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
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Stephen F. Madden
Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Alessandra Di Grande
Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Yue Fan
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
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Sudipto Das
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Oscar M. Rueda
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
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  • ORCID record for Oscar M. Rueda
Catríona M. Dowling
Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Damir Varešlija
Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
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  • ORCID record for Damir Varešlija
Suet-Feung Chin
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
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Sabine Linn
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Leonie S. Young
Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Karin Jirström
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
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John P. Crown
Department of Medical Oncology, Dublin, Ireland.
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Rene Bernards
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Carlos Caldas
Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, England.
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William M. Gallagher
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
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Darran P. O'Connor
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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  • For correspondence: darranoconnor@rcsi.com
Tríona Ní Chonghaile
Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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DOI: 10.1158/1078-0432.CCR-19-0713 Published December 2019
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2019;25:7139–50

  • Received February 27, 2019.
  • Revision received June 13, 2019.
  • Accepted August 7, 2019.
  • Published first August 13, 2019.
  • ©2019 American Association for Cancer Research.
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Clinical Cancer Research: 25 (23)
December 2019
Volume 25, Issue 23
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BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
Louise Walsh, Kathryn E. Haley, Bruce Moran, Brian Mooney, Finbarr Tarrant, Stephen F. Madden, Alessandra Di Grande, Yue Fan, Sudipto Das, Oscar M. Rueda, Catríona M. Dowling, Damir Varešlija, Suet-Feung Chin, Sabine Linn, Leonie S. Young, Karin Jirström, John P. Crown, Rene Bernards, Carlos Caldas, William M. Gallagher, Darran P. O'Connor and Tríona Ní Chonghaile
Clin Cancer Res December 1 2019 (25) (23) 7139-7150; DOI: 10.1158/1078-0432.CCR-19-0713

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BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
Louise Walsh, Kathryn E. Haley, Bruce Moran, Brian Mooney, Finbarr Tarrant, Stephen F. Madden, Alessandra Di Grande, Yue Fan, Sudipto Das, Oscar M. Rueda, Catríona M. Dowling, Damir Varešlija, Suet-Feung Chin, Sabine Linn, Leonie S. Young, Karin Jirström, John P. Crown, Rene Bernards, Carlos Caldas, William M. Gallagher, Darran P. O'Connor and Tríona Ní Chonghaile
Clin Cancer Res December 1 2019 (25) (23) 7139-7150; DOI: 10.1158/1078-0432.CCR-19-0713
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Clinical Cancer Research
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