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

Walsh, Louise ; Haley, Kathryn E ; Moran, Bruce ; Mooney, Brian ; Tarrant, Finbarr ; Madden, Stephen F ; Di Grande, Alessandra ; Fan, Yue ; Das, Sudipto and Rueda, Oscar M , et al. (2019) In Clinical cancer research : an official journal of the American Association for Cancer Research 25(23). p.7139-7150
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... (More)

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.

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keywords
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
in
Clinical cancer research : an official journal of the American Association for Cancer Research
volume
25
issue
23
pages
7139 - 7150
publisher
American Association for Cancer Research
external identifiers
  • scopus:85076198485
  • pmid:31409615
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-19-0713
language
English
LU publication?
yes
additional info
©2019 American Association for Cancer Research.
id
b0e5bdc3-31cb-470a-a292-b94d7bcd9fc8
date added to LUP
2023-09-13 12:16:01
date last changed
2024-02-20 01:10:06
@article{b0e5bdc3-31cb-470a-a292-b94d7bcd9fc8,
  abstract     = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Walsh, Louise and Haley, Kathryn E and Moran, Bruce and Mooney, Brian and Tarrant, Finbarr and Madden, Stephen F and Di Grande, Alessandra and Fan, Yue and Das, Sudipto and Rueda, Oscar M and Dowling, Catríona M and Varešlija, Damir and Chin, Suet-Feung and Linn, Sabine and Young, Leonie S and Jirström, Karin and Crown, John P and Bernards, Rene and Caldas, Carlos and Gallagher, William M and O'Connor, Darran P and Ní Chonghaile, Tríona}},
  issn         = {{1078-0432}},
  keywords     = {{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}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{23}},
  pages        = {{7139--7150}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Clinical cancer research : an official journal of the American Association for Cancer Research}},
  title        = {{BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-19-0713}},
  doi          = {{10.1158/1078-0432.CCR-19-0713}},
  volume       = {{25}},
  year         = {{2019}},
}