Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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E2 MODULATION OF TUMORIGENESIS IN ERBB2 TRANSGENIC MICE


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The erbB-2 (neu/HER-2) oncogene is amplified and the protein overexpressed in 30-60 percent of human breast carcinomas. erbB- 2 associated pro-carcinogenic effects occur in concert with a myriad of other cellular disturbances, including molecular and transcriptional alterations. The combined effects of these changes are difficult to study in human samples because of their static nature and other tissue limitations. Utilization of virgin MMTV wt erbB-2 transgenic mice, which are genetically susceptible to breast cancer, provide a unique opportunity to study the effects of altered erbB-2 over time in vivo. Alterations of at least 3 genes commonly assoicated with human breast carcinoma (erbB-2, epidermal growth factor receptor (EGFR) and p53) have been observed in tumors that arise in these animals. Our data suggests that 17-beta-estradiol (E2) administration modulates carcinogenesis in this model system, with acceleration of mammary epithelial hyperplasia and dysplasia. Downregulation of the estrogen receptor (ER) followed by expression of erbB-2, activated erbB-2 and EGFR by benign breast epithelium was noted within weeks of continuous E2 administration, often in concert with hyperplasia and atypical hyperplastic lobulo-alveolar units. Cancers which arose with E2 supplementation (and novel tumor cell lines from these tumors) had phenotypic, biologic and molecular differences (ER negative, marked EGFR expression) compared to those from non-treated animals (ER positive, low EGFR expression); all showed erbB-2 abnormalities. E2 treated animals developed cancers somewhat earlier although differences in breast cancer incidence were not significant by 25-30 weeks. Our specific aims are: 1) To study the relationship between dose and duration of estradiol (E2) supplementation and mammary hyperplasia, dysplasia and carcinogenesis in virgin MMTV wt erbB- 2 transgenic mice; 2) To determine the effect of blocking erbB-2, EGFR and ER function, individually or in combination, to evaluate the contributions of each to the process of epithelial carcinogenesis in E2 treated and untreated animals; 3) To study differences in biological behavior and protein expression of benign, dysplastic and malignant mammary epithelial cells and derived lines from aims 1 and 2; and 4) To evaluate genetic mutations and dysregulated gene expression in mouse carcinomas and derived lines with and without estrogenic modulation. Utilization of this model will provide developmental, expression and molecular data associated with estrogen/estrogen receptor and tyrosine kinase receptor/ligand growth promoted breast carcinogenesis.
Collapse sponsor award id
R01CA082848

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Collapse start date
1999-08-15
Collapse end date
2005-05-31

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