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

• Type of Material: Article
• Authors: DJ Brennan, University College Dublin; DP O'Connor, University College Dublin; H Laursen, University College Dublin; SF McGee, University College Dublin; S McCarthy, University College Dublin; R Zagozdzon, University College Dublin; E Rexhepaj, University College Dublin; AC Culhane, Harvard University; FM Martin, University College Dublin; MJ Duffy, University College Dublin; G Landberg, Lund University; L Ryden, Lund University; SM Hewitt, NCI; Michael J Kuhar, Emory University; R Bernards, Netherlands Cancer Institute; RC Millikan, University of North Carolina; JP Crown, St Vincents Univ Hosp; K Jirstrom, Lund University; WM Gallagher, University College Dublin
• Language: English
• Date: 2012-07-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Macmillan Publishers Limited.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2011.519
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 31
• Issue: 30
• Start Page: 3483
• End Page: 3494
• Grant/Funding Information: Funding is acknowledged from the Health Research Board of Ireland, Enterprise Ireland and the Science Foundation Ireland Strategic Research Cluster award to Molecular Therapeutics for Cancer Ireland (08/SRC/B1410).; The work of Dr R Zagozdzon has been supported by a Marie Curie International Reintegration Grant no. 224865 within the 7th European Community Framework Program.; Dr MJ Kuhar is funded by RR00165.; The UCD Conway Institute is funded by the Program for Third Level Institutions, as administered by the Higher Education Authority of Ireland.
• Keywords: Life Sciences & Biomedicine; Oncology; GENE-EXPRESSION; TAMOXIFEN; breast cancer; CART PEPTIDES; Genetics & Heredity; NERVE GROWTH-FACTOR; PHOSPHORYLATION; prognosis; CELLS; estrogen receptor; ESTROGEN-RECEPTOR; RANDOMIZED-TRIALS; THERAPY; Cell Biology; Science & Technology; Biochemistry & Molecular Biology; cocaine- and amphetamine-regulated transcript; PROTEIN-KINASE
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Wi thin 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 ERα 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.