Investigating the Role of Cooperative Interactions Between the Neu Protooncogene and the Other erbB Family Members in Rat Mammary Carcinogenesis

Abstract

Abstract : In order to generate a rat model of neu-induced mammary carcinogenesis, we have created transgenic rats that utilize the mouse mammary tumor virus promoter to overexpress the rat neu proto-oncogene in the mammary gland. A nuclease protection assay was used to quantify the relative overexpression of neu message within the mammary gland and rats of both sexes were observed until at least 14 months of age. In the most characterized line (line 6500), transgenic virgin females and males at 12 weeks of age overexpressed neu in the mammary gland. The expression level of neu was equal between the two sexes. Despite this neu overexpression, mammary carcinomas did not develop in any of the transgenic virgin females at 14 months or 18 months. In striking contrast to the females, 77.8% and 100% of the transgenic males developed mammary carcinomas at 14 and 18 months of age, respectively. Sequence analysis from 13 of the mammary carcinomas revealed that the neu transgene had not undergone any spontaneous mutations in the transmembrane domain and adjacent extracellular domain, regions which have been reported to be mutated in neu transgenic mice. To assess the role of hormones in the observed mammary carcinogenesis, both male and females were gonadectomized at 8 weeks of age and sacrificed at 14 months of age. Mammary carcinomas did not develop in any of the castrated transgenic males while 100% of the intact transgenic males developed multiple mammary carcinomas. Transgenic females did not develop mammary carcinomas regardless of gonadal status. These results suggest that in the context of HER2/neu overexpression, androgens may be powerful promoters of mammary carcinogenesis.