title: Co-expression of MET and CD47 is a novel prognosticator for survival of luminal breast cancer patients.
abstract: Although luminal-type primary breast cancer can be efficiently treated, development of metastatic disease remains a significant clinical problem. We have previously shown that luminal-type circulating tumor cells (CTCs) co-expressing the tyrosine-kinase MET and CD47, a ligand involved in cancer cell evasion from macrophage scavenging, are able to initiate metastasis in xenografts. Here, we investigated the clinical relevance of MET-CD47 co-expression in 255 hormone receptor positive breast tumors by immunohistochemistry and found a 10.3- year mean overall-survival difference between MET-CD47 double-positive and double-negative patients (p<0.001) MET-CD47 co-expression defined a novel independent prognosticator for overall-survival by multivariate analysis (Cox proportional hazards model: HR: 4.1, p<0.002) and CD47 expression alone or in combination with MET was strongly associated with lymph node metastasis. Furthermore, flow cytometric analysis of metastatic patient blood revealed consistent presence of MET+CD47+ CTCs (range 0.8 - 33.3% of CTCs) and their frequency was associated with increased metastatic spread. Finally, primary uncultured CTCs with high MET+CD47+ content showed an enhanced capacity to initiate metastasis in mice. Detection and targeting of MET and CD47 may thus provide a rational basis for risk stratification and treatment of patients with luminal-type breast cancer.
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Irène
authors.initials: I
authors.lastname: Baccelli
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Vogel
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Berit Maria
authors.initials: BM
authors.lastname: Pfitzner
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Klein
authors.affiliation: National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wallwiener
authors.affiliation: National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Scharpff
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Massimo
authors.initials: M
authors.lastname: Saini
authors.affiliation: Department of Biostatistics, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld TP4, 69120 Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Holland-Letz
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Sinn
authors.affiliation: National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany. National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D051928:CD47 Antigen / Q000032:analysis*; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D015999:Multivariate Analysis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis*; D012189:Retrospective Studies; D012307:Risk Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D051928:CD47 Antigen; C497894:CD47 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met