Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma.
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.
Wechselberger
Christian
C
Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, MD 20892, USA.
Strizzi
Luigi
L
Kenney
Nicholas
N
Hirota
Morihisa
M
Sun
Youping
Y
Ebert
Andreas
A
Orozco
Olivia
O
Bianco
Caterina
C
Khan
Nadia I
NI
Wallace-Jones
Brenda
B
Normanno
Nicola
N
Adkins
Heather
H
Sanicola
Michele
M
Salomon
David S
DS
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*
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