Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma

Oncogene. 2005 Jun 9;24(25):4094-105. doi: 10.1038/sj.onc.1208417.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Animals
  • Cell Division
  • DNA Primers
  • DNA, Complementary / genetics
  • Epidermal Growth Factor / genetics*
  • Female
  • GPI-Linked Proteins
  • Growth Substances / genetics
  • Hyperplasia
  • Intercellular Signaling Peptides and Proteins
  • Mammary Glands, Animal / pathology*
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / pathology
  • Membrane Glycoproteins / genetics*
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins / genetics*


  • DNA Primers
  • DNA, Complementary
  • GPI-Linked Proteins
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • TDGF1 protein, human
  • Epidermal Growth Factor