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The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ER alpha, and is an independent prognostic factor in node-negative breast cancer

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Author

  • D. J. Brennan
  • D. P. O'Connor
  • H. Laursen
  • S. F. McGee
  • S. McCarthy
  • R. Zagozdzon
  • E. Rexhepaj
  • A. C. Culhane
  • F. M. Martin
  • M. J. Duffy
  • Göran Landberg
  • Lisa Rydén
  • S. M. Hewitt
  • M. J. Kuhar
  • R. Bernards
  • R. C. Millikan
  • J. P. Crown
  • Karin Jirström
  • W. M. Gallagher
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Summary, in English

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n = 690; P = 0.002, 0.013). We also show that CART increases the transcriptional activity of ER alpha in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy. Oncogene (2012) 31, 3483-3494; doi:10.1038/onc.2011.519; published online 5 December 2011

Department/s

Publishing year

2012

Language

English

Pages

3483-3494

Publication/Series

Oncogene

Volume

31

Issue

30

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cancer and Oncology

Keywords

  • cocaine- and amphetamine-regulated transcript
  • breast cancer
  • prognosis
  • estrogen receptor

Status

Published

Research group

  • Pathology, Malmö

ISBN/ISSN/Other

  • ISSN: 1476-5594