Identification of Oncogenes Cooperating in Murine Mammary Tumorigenesis

Abstract

In order to identify and characterize additional novel or unexpected proto-oncogenes that, in addition to fibroblast growth factors (Fgfs) cooperate with Wntl in murine mammary tumorigenesis, we have generated MMTV-infected Wnt10b/Fgfr2DN, Wntl/Fgfr2DN and Wntl/FgP bitransgenic mice. In the first two models, the Wnt oncogenic signal is constitutively overexpressed in their mammary gland, cooperative oncogenic Fgf signals should be abolished by the expression of a dominant-negative FOF receptor (Fgfr2DN) The Wntl/Fgf3 model displays constitutive overexpression of both Wnt and Fgfoncogenic signals. In all three models, only those cells carrying MMTV-insertionally activated cellular proto-oncogenes, other than Wnts and Fgfs, should have a growth advantage in the bitransgenic mammary gland. The clonal expansion of these cells leads to mammary tumorigenesis. As proposed, we have generated cohorts of 20-25 MMTV-infected Wnt1Ob/Fgfr2DN, Wnt1/Fgfr2DN and Wntl/Fgf3 bitransgenic females. As controls, we have also generated uninfected bitransgenic cohort, as well as MMTV-infected and uninfected monotrausgenic female control groups. To date, multiple mammary adenocarcinomas have appeared in the MMTV-infected bitransgenic animals. These tumors appeared with a mean latency of 5.4 and 3 months in Wntl/Fgfr2DN and Wnt1/Fgf3 females respectively. Wnt1Ob/Fgfr2DN tumor histopathology corresponded to papillary lobular, ductal, and metaplastic invasive carcinomas. Wnt1/Fgfr2DN tumors were mainly papillary carcinomas, and Wnt1/Fgf3 tumors displayed features of highly metastatic (to lungs) papillary carcinomas. At least 1OWntlOb/Fgfr2DN, 6Wntl/Fgfr2DN and 1 Wnt1/Fgf3 tumors carry newly integrated MMTV proviruses. Our current efforts are to clone and identify these genes, and we are also screening for additional candidate tumors.

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Document Details

Document Type
Technical Report
Publication Date
Jun 01, 2002
Accession Number
ADA409479

Entities

People

  • Gregory M. Shackleford
  • Rocio S. Lopez-diego

Organizations

  • Children's Hospital Los Angeles

Tags

DTIC Thesaurus Topics

  • Abstracts
  • Biomedical Research
  • Breast Cancer
  • California
  • Cancer
  • Carcinoma
  • Cells
  • Demographic Cohorts
  • Epithelial Cells
  • Health Services
  • Identification
  • Infection
  • Mammary Glands
  • Neoplasms
  • Polymerase Chain Reaction
  • Viruses
  • Wound Infections

Fields of Study

  • Biology

Readers

  • Breast cancer cell signaling and growth regulation.
  • Molecular Biology and Genetics