Studying the Roles of GRK2-Mediated Smad2/3 Phosphorylation as a Negative Feedback Mechanism of TGF-Beta Signaling and a Target of Breast Cancer Therapeutics
Abstract
The canonical TGFb/Smad signaling axis promotes breast cancer metastasis, as blocking this pathway could slow down metastasis in animal models. Since Smad2 and Smad3 are transcription factors, they are not ideal drug targets. As such, investigating intracellular signaling mechanisms that regulate Smad activity is highly meaningful not only for understanding TGFb s pro-invasive functions in breast cancer but also for identifying new leads to design therapies that block TGFb signaling in metastatic breast cancer. We identify two of such mechanisms, mediated through cell signaling molecules GRK2 and BCAR3, which could antagonize TGFb signaling in human breast cancer cells. During the tenure of the traineeship, we performed biochemical studies to elucidate how these signaling molecules could block TGFb/Smad signaling; and performed cell-based functional analysis to determine whether these molecules could modulate TGFb s pro-invasive functions. We found that both GRK2 and BCAR3 were potent inhibitory molecules of Smad activation. They both antagonize TGFb-mediated gene transcription and TGFb-induced breast cancer cell invasion. High expression of GRK2, or BCAR3, associates with lower chance of relapse and distant metastasis among breast cancer patients. As such, mimicking GRK2 or BCAR3 s function in breast cancer cells could likely decrease the invasive properties of these cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2014
- Accession Number
- ADA598780
Entities
People
- Jimin Guo
Organizations
- McGill University