title: The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.
abstract: 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.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: D J
authors.initials: DJ
authors.lastname: Brennan
authors.forename: D P
authors.initials: DP
authors.lastname: O'Connor
authors.forename: H
authors.initials: H
authors.lastname: Laursen
authors.forename: S F
authors.initials: SF
authors.lastname: McGee
authors.forename: S
authors.initials: S
authors.lastname: McCarthy
authors.forename: R
authors.initials: R
authors.lastname: Zagozdzon
authors.forename: E
authors.initials: E
authors.lastname: Rexhepaj
authors.forename: A C
authors.initials: AC
authors.lastname: Culhane
authors.forename: F M
authors.initials: FM
authors.lastname: Martin
authors.forename: M J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: G
authors.initials: G
authors.lastname: Landberg
authors.forename: L
authors.initials: L
authors.lastname: Ryden
authors.forename: S M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: M J
authors.initials: MJ
authors.lastname: Kuhar
authors.forename: R
authors.initials: R
authors.lastname: Bernards
authors.forename: R C
authors.initials: RC
authors.lastname: Millikan
authors.forename: J P
authors.initials: JP
authors.lastname: Crown
authors.forename: K
authors.initials: K
authors.lastname: Jirström
authors.forename: W M
authors.initials: WM
authors.lastname: Gallagher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011379:Prognosis; D013629:Tamoxifen / Q000627:therapeutic use; D014158:Transcription, Genetic; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009419:Nerve Tissue Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D013629:Tamoxifen