|HADSELL, DARRYL - BAYLOR COLL OF MEDICINE|
|Murphy, Kristin - BAYLOR COLL OF MEDICINE|
|Reece, Naomi - BAYLOR COLL OF MEDICINE|
|Laucirica, Rodolfo - BAYLOR COLL OF MEDICINE|
|Rosen, Jeffrey - BAYLOR COLL OF MEDICINE|
Submitted to: Oncogene
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 2, 1999
Publication Date: N/A
Interpretive Summary: Insulin-like growth factor-I (IGF-I) is a hormone in the body that is involved with normal mammary gland development, but it also has been found to play a role in breast cancer. We wanted to determine if IGF-I, overexpressed in the mammary gland, would cause cancer in mice. Another aspect of our study pertained to a protein called p53, a tumor suppressor gene that has been found to be mutated in half of all human cancers. Evidence suggests there is a regulatory axis between IGF-I and p53 that controls cell growth and death. We wanted to find out whether mammary tumors would form at a faster rate if we disrupted this axis by overexpressing mutant p53 in the presence of IGF-I. Our results, in a special mouse model, showed that overexpression of IGF-I in the mammary gland inhibits normal cell death and increases the frequency of random mammary tumors, and interactions with mutant p53 dramatically increase the susceptibility of mammary tissue to cancer. Thus, the results support the conclusion that disruption of the p53/IGF-I axis accelerates the rate of tumor formation in the mammary gland. This study provides important information toward better understanding and treatment of breast cancer.
Technical Abstract: The objective of these studies was to analyze mammary tumorigenesis in transgenic mice which overexpress des(1-3)hIGF-I (WAP-DES) and/or a mutant form of p53 (p53**172R-H**). Mammary tissue from nonlactating, multiparous WAP-DES mice exhibited hyperplastic lesions which constitutively expressed WAP-DES. By 23 months of age, 53% of the transgenic mice developed adenocarcinomas. To determine the effects of WAP-DES on the normal mammary gland, TUNEL and BRDU staining was conducted on mammary tissue. This analysis demonstrated a 75% reduction in both apoptosis and BrdU labeling due to WAP-DES expression. Tumor incidence in bigenic mice was similar to that of WAP-DES and two- to threefold greater than that of nontransgenic and p53**172R-H** females. Tumor latency was 8 months shorter in bigenic mice than in mice of the other three genotypes. Aneuploidy was frequently observed in tumors from bigenic and p53**172R-H**, but not from WAP-DES mice. Expression of IGFBP3 was elevated in tumors from WAP-DES, but not bigenic mice, indicating an alteration in the p53/IGF-I axis. These studies support the conclusion that overexpression of des(1-3)hIGF-I increases the frequency of stochastic mammary tumors and that the progression of these tumors can be accelerated by interaction with mutant p53**172R-H**. This cooperation likely involves disruption of the normal p53/IGF-I axis and genomic destabilization.