Accession Number : ADA335188

Title :   Mechanisms of Murine Mammary Tumorigenesis: Cooperation Between Tyrosine Kinase Receptors and Mutant p53.

Descriptive Note : Annual rept. 1 Aug 96-31 Jul 97

Corporate Author : YALE UNIV NEW HAVEN CT SCHOOL OF MEDICINE

Personal Author(s) : Perkins, Archibald

PDF Url : ADA335188

Report Date : AUG 1997

Pagination or Media Count : 27

Abstract : Transgenic mice expressing ErbB2 develop mammary tumors with a latency of over 200 days. We were interested in examining the cooperation between mutant p53 and ErbB2. We examined mammary tumors arising in MMTV-ErbB2 transgenic mice for mutations in exons 4-8 of p53 by direct sequencing of PCR products, and have found that 37% of tumors have a missense mutation at codon 256, which converts an Asp to Asn. We have directly tested for cooperativity between ErbB2 and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MMTV-ErhB2 and p53-172Arg-His. Bitransgenic mice expressing ErhB2 and p53-172Arg-His develop mammary tumors with a latency of 154 d, where mice expressing ErbB2 alone develop tumors with a latency of 234 d. Tumors arising in the p53/ErbB2 bitransgenic mice show large cell size, marked nuclear pleiomorphism, high mitotic rate, abnormal mitotic figures, and increased apoptosis. Ploidy analysis revealed that while tumors arising in the ErbB2 mice were diploid, tumors arising in the p53/ErbB2 bitransgenic mice comprised aneuploid cells. Analysis of these tumors revealed the absence of activating mutations in the ErbB2 transgene, while analysis of the ErbB2 receptor shows that the receptor is highly phosphorylated. These data indicate that p53 mutation is an important cooperating event in ErbB2-mediated oncogenesis.

Descriptors :   *NEOPLASMS, *MUTATIONS, *MAMMARY GLANDS, *TYROSINE, *BREAST CANCER, ACTIVATION, HIGH RATE, SIZES(DIMENSIONS), CELLS, MICE, ABNORMALITIES, MITOSIS.

Subject Categories : Anatomy and Physiology

Distribution Statement : APPROVED FOR PUBLIC RELEASE