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

• Published in: Oncogene Vol. 31; no. 30; pp. 3483 - 3494
• Main Authors: Brennan, D J, O'Connor, D P, Laursen, H, McGee, S F, McCarthy, S, Zagozdzon, R, Rexhepaj, E, Culhane, A C, Martin, F M, Duffy, M J, Landberg, G, Ryden, L, Hewitt, S M, Kuhar, M J, Bernards, R, Millikan, R C, Crown, J P, Jirström, K, Gallagher, W M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.07.2012; Nature Publishing Group
• Subjects: 631/80/86; 692/699/67/1347; 692/699/67/1857; 692/700/1750; Adjuvants; Adult; Aged; Aged, 80 and over; Amphetamines; Antineoplastic Agents, Hormonal - therapeutic use; Apoptosis; Apoptosis - drug effects; Autocrine signalling; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer and Oncology; Cancer och onkologi; Cell Biology; Cell death; Cell Line, Tumor; Chemotherapy; Clinical Medicine; Cocaine; cocaine- and amphetamine-regulated transcript; Cocaine- and amphetamine-regulated transcript protein; Cohort Studies; DNA microarrays; estrogen receptor; Estrogen Receptor alpha - metabolism; Estrogen receptors; Female; Gene expression; Genetic aspects; Human Genetics; Humans; Image processing; Image Processing, Computer-Assisted; Internal Medicine; Kinases; Klinisk medicin; Ligands; Lymph; Lymph nodes; Lymphatic system; MAP kinase; MAP Kinase Signaling System; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Metastases; Middle Aged; Nerve Tissue Proteins - metabolism; Oncology; original-article; Paracrine signalling; Physiological aspects; Precision medicine; Prognosis; Protein kinase; Risk groups; Tamoxifen; Tamoxifen - therapeutic use; Transcription; Transcription factors; Transcription, Genetic; Tumor cell lines; Tumor cells; Tumors; breast cancer; cocaine- and amphetamine-regulated transcript; estrogen receptor; prognosis
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/onc.2011.519

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 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.