Date of Award
Doctor of Philosophy (PhD)
Dr. John A. Hassell
The ets genes encode DNA-binding proteins capable of regulating the expression of target genes that contain ETS sites within their promoter sequences. The ets gene PEA3 is overexpressed in a majority of human breast tumour samples, as well as in the mammary tumours and lung metastases of several transgenic mouse models of this disease. The Pea3 subfamily genes, which include Pea3, Erm, and Er81, are expressed during mouse mammary gland development. However, in mammary tumours induced by the HER2/Neu receptor tyrosine kinase, the Pea3 subfamily genes were upregulated by five-two twenty-fold as compared to normal mammary tissue of wild-type control mice. To understand the role of the PEA3 subfamily proteins in mammary tumorigenesis, transgenic mice were generated which overexpress either PEA3 or a dominant-negative mutant of PEA3 (∆NPEA3En) under the transcritional control of the mouse mammary tumour virus (MMTV) promoter/enhancer. ∆NPEA3En was able to inhibit the function of all three PEA3 subfamily proteins and reduce oncogenic Neu-induced transformation of mouse fibroblasts in cell culture-based assays. ∆NPEA3En was able to delay tumour formation as well as reduce the number and the size of tumours that developed in MMTV-neu/∆NPEA3En bi-transgenic mice as compared to MMTV-neu transgenic female mice. The tumours that did form in bi-transgenic mice generally lacked ∆NPEA3En expression indicating that PEA3 subfamily function is required for tumour progression. The mammary gland of MMTV-PEA3 transgenic female mice exhibited increased ductal branching and side bud formation in virgin mice, and decreased lobuloalveolar differentiation during pregnancy. Surprisingly, MMTV-neu/PEA3 bi-transgenic mice had a longer latency in mammary tumour formation than did MMTV-neu female mice, similar to what was observed in MMTV-neu/∆PEA3 bi-transgenic mice had a longer latency in mammary tumour formation than did MMTV-neu/∆NPEA3En bi-transgenic mice. These results implicate PEA3 subfamily protein function during mammary gland development and in Neu-induced mammary tumorigenesis. Thus, inhibiting PEA3 subfamily protein function, or that of one or more specific target gene products, may complement other current therapies in the treatment of human breast cancer
SHEPHERD, TREVOR G., "THE ROLE OF THE PEA3 SUBFAMILY ETS GENES IN MAMMARY TUMORIGENESIS: USE OF TRANSGENIC MOUSE MODELS OF BREAST CANCER" (2002). Open Access Dissertations and Theses. Paper 1387.