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Delineating Transcriptional Networks of Prognostic Gene Signatures Refines Treatment Recommendations for Lymph Node-negative Breast Cancer Patients.

Lanigan, Fiona; Brien, Gerard L; Fan, Yue; Madden, Stephen F; Jerman, Emilia; Aloraifi, Fatima; Hokamp, Karsten; Dunne, Eiseart J; Lohan, Amanda J and Flanagan, Louise, et al. (2015) In The FEBS Journal 282(18). p.3455-3473
Abstract
The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics following surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. Here, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer... (More)
The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics following surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. Here, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer better than currently used multi-gene prognostic assays, particularly in lymph node-negative, estrogen receptor-positive patients. Simultaneous examination of p16(INK) (4A ) expression, which predicts tumors that have bypassed cellular senescence, revealed that intermediate levels of p16(INK) (4A) correlate with an intact pRB pathway and improved survival. A combination of these master transcriptional regulators and p16(INK) (4A) , termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy. Furthermore, OncoMasTR accurately classifies over 60% of patients as 'low risk', an improvement on existing prognostic assays, which has the potential to reduce overtreatment in early-stage patients. Taken together, this study provides new insights into the transcriptional regulation of cellular proliferation in breast cancer and provides an opportunity to enhance and streamline breast cancer prognosis. This article is protected by copyright. All rights reserved. (Less)
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The FEBS Journal
volume
282
issue
18
pages
3455 - 3473
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
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  • pmid:26094870
  • wos:000362364800001
  • scopus:84941936960
ISSN
1742-464X
DOI
10.1111/febs.13354
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English
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df6e70b2-7f64-486c-aee5-9de85d220230 (old id 7484353)
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http://www.ncbi.nlm.nih.gov/pubmed/26094870?dopt=Abstract
date added to LUP
2015-07-09 19:24:07
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2017-05-28 03:01:55
@article{df6e70b2-7f64-486c-aee5-9de85d220230,
  abstract     = {The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics following surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. Here, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer better than currently used multi-gene prognostic assays, particularly in lymph node-negative, estrogen receptor-positive patients. Simultaneous examination of p16(INK) (4A ) expression, which predicts tumors that have bypassed cellular senescence, revealed that intermediate levels of p16(INK) (4A) correlate with an intact pRB pathway and improved survival. A combination of these master transcriptional regulators and p16(INK) (4A) , termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy. Furthermore, OncoMasTR accurately classifies over 60% of patients as 'low risk', an improvement on existing prognostic assays, which has the potential to reduce overtreatment in early-stage patients. Taken together, this study provides new insights into the transcriptional regulation of cellular proliferation in breast cancer and provides an opportunity to enhance and streamline breast cancer prognosis. This article is protected by copyright. All rights reserved.},
  author       = {Lanigan, Fiona and Brien, Gerard L and Fan, Yue and Madden, Stephen F and Jerman, Emilia and Aloraifi, Fatima and Hokamp, Karsten and Dunne, Eiseart J and Lohan, Amanda J and Flanagan, Louise and Garbe, James C and Stampfer, Martha R and Fridberg, Marie and Jirström, Karin and Quinn, Cecily M and Loftus, Brendan and Gallagher, William M and Geraghty, James and Bracken, Adrian P},
  issn         = {1742-464X},
  language     = {eng},
  number       = {18},
  pages        = {3455--3473},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {The FEBS Journal},
  title        = {Delineating Transcriptional Networks of Prognostic Gene Signatures Refines Treatment Recommendations for Lymph Node-negative Breast Cancer Patients.},
  url          = {http://dx.doi.org/10.1111/febs.13354},
  volume       = {282},
  year         = {2015},
}