SHC Functions in the Development and Transformation of the Mouse Mammary Gland

Abstract

The adapter protein Shc is a ubiquitously expressed Src homology 2 (SH2) domain protein implicated in the transmission of activation signals to Ras. She proteins become phosphorylated on tyrosine in cells stimulated with a variety of growth factors and in v-𝘴𝘳𝘤 transformed cells and are able to transform fibroblasts and differentiate PC12 cells in a Ras-dependent fashion. To assess the transforming ability of Shc in the mouse mammary gland, I generated transgenic mice harbouring the p52ˢʰᶜ cDNA under the transcriptional control of the mouse mammary tumor virus long terminal repeat (MMTV LTR). While p52ˢʰᶜ expression was correlated with multiple enlarged terminal end buds in virgin mouse mammary glands, multiparous mice developed mammary hyperplasias and mammary carcinomas. The frequency, latency and focal nature with which these tumors arose suggests that additional events are necessary to induce malignant conversion of primary mammary epithelial cells. To directly test the role of Shc in established mammary tumor models, I have generated two strains of bigenic mice. When Shc was overexpressed with NDL 1-2, a constitutively activated form of the Neu receptor tyrosine kinase, latency of tumor onset was decreased over that of parental MMTV/NDL 1-2 mice. Polyomavirus middle T antigen (PyV MT) mutants with a functionally inactive Shc binding site (MT Y250F) are debilitated in mammary tumor formation compared to wild-type PyV MT transgenic animals. Concurrent overexpression of Shc with MT Y250F accelerated tumor kinetics and increased the propensity for metastasis to the lungs of bigenic animals.