Murine Models of Breast Cancer: Assessment of the Role of c-Src in Mammary Tumorigenesis
Abstract
Strong evidence exists that the c-Src non-receptor tyrosine kinase plays a role in the pathology of human breast tumors. The purpose of this study is to examine the role of c-Src in mammary tumorigenesis and elucidate the mechanisms that lead to tumor formation in an animal model for breast cancer. In our previous experiments we used Src substrates that we cloned to activate c-Src and study its signaling mechanisms. Using one of these substrates, Sin, we characterized a signaling cascade that is activated as a result of Sin binding to Src and Src- mediated Sin phosphorylation. We found that Src-phosphorylated Sin recruits a signaling complex that leads to the activation of the small GTP-binding protein Rap 1. Rap 1 then activates the ERK kinase that in turn mediates Src-dependent transcriptional activation. In addition, when we compared Sin-activated wild-type Src and an oncogenic Src protein we found that their signaling mechanisms differed in that, wild type Src signaling is mediated by the Rap 1 cascade whereas oncogenic Src signaling is mediated by Rap 1, as well as another G- protein, Ras. Our results for the first time implicate the Rap1 pathway in wild type and oncogenic Src signaling and reveal mechanistic differences in the signaling mechanisms of these proteins. In our future experiments we will address the role of Rap1 activation in cellular transformation and mammary tumorigenesis in cell lines and transgenic mice coexpressing Src and Sin. These experiments will provide insight into the mechanisms of Src- mediated tumorigenesis and may lead to the identification of proteins that will be used as targets for drug development.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2000
- Accession Number
- ADA388873
Entities
People
- Konstantina Alexandropoulos
Organizations
- Columbia University