title: Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma.
abstract: Human Cripto-1 (CR-1) is overexpressed in approximately 80% of human breast, colon and lung carcinomas. Mouse Cr-1 upregulation is also observed in a number of transgenic (Tg) mouse mammary tumors. To determine whether CR-1 can alter mammary gland development and/or may contribute to tumorigenesis in vivo, we have generated Tg mouse lines that express human CR-1 under the transcriptional control of the mouse mammary tumor virus (MMTV). Stable Tg MMTV/CR-1 FVB/N lines expressing different levels of CR-1 were analysed. Virgin female MMTV/CR-1 Tg mice exhibited enhanced ductal branching, dilated ducts, intraductal hyperplasia, hyperplastic alveolar nodules and condensation of the mammary stroma. Virgin aged MMTV/CR-1 Tg mice also possessed persistent end buds. In aged multiparous MMTV/CR-1 mice, the hyperplastic phenotype was most pronounced with multifocal hyperplasias. In the highest CR-1-expressing subline, G4, 38% (12/31) of the multiparous animals aged 12-20 months developed hyperplasias and approximately 33% (11/31) developed papillary adenocarcinomas. The long latency period suggests that additional genetic alterations are required to facilitate mammary tumor formation in conjunction with CR-1. This is the first in vivo study that shows hyperplasia and tumor growth in CR-1-overexpressing animals.
authors.affiliation: Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Wechselberger
authors.forename: Luigi
authors.initials: L
authors.lastname: Strizzi
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kenney
authors.forename: Morihisa
authors.initials: M
authors.lastname: Hirota
authors.forename: Youping
authors.initials: Y
authors.lastname: Sun
authors.forename: Andreas
authors.initials: A
authors.lastname: Ebert
authors.forename: Olivia
authors.initials: O
authors.lastname: Orozco
authors.forename: Caterina
authors.initials: C
authors.lastname: Bianco
authors.forename: Nadia I
authors.initials: NI
authors.lastname: Khan
authors.forename: Brenda
authors.initials: B
authors.lastname: Wallace-Jones
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
authors.forename: Heather
authors.initials: H
authors.lastname: Adkins
authors.forename: Michele
authors.initials: M
authors.lastname: Sanicola
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D002455:Cell Division; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins; D006133:Growth Substances / Q000235:genetics; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins; D008321:Mammary Glands, Animal / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics*
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D058851:GPI-Linked Proteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; D004815:Epidermal Growth Factor