Role of Abl in Suppressing Breast Cancer Progression Stimulated by TGF-beta
Abstract
Transforming growth factor-Beta (TGF-Beta) is a ubiquitous cytokine with dual roles in tumor suppression and promotion, and these dichotomous functions have frustrated the development of therapies targeting oncogenic signaling by TGF-Beta. In comparison, Abl kinase is well established as a driver of tumorigenesis in hematopoietic cancers; however, a clear role for Abl in regulating solid tumor development remains elusive. Here we investigated the role of Abl in TGF-Beta-mediated epithelial-mesenchymal transition (EMT) in normal and metastatic mammary epithelial cells (MECs). In doing so, we discovered Abl as being a critical regulator of MEC morphology and showed that Abl inactivation was sufficient to induce phenotypic and transcriptional EMT in normal MECs. Increasing Abl activity in metastatic MECs resulted in complete morphological reversion, restored cytostatic TGF-Beta signaling, and blocked TGF-Beta-induced matrix metalloproteinase secretion. Expressing constitutively-active Abl in TGF-Beta-responsive metastatic MECs blocked tumorigenisis in vivo. Accordingly, we found Imatinib therapy to provide no clinical benefit in the treatment of breast cancer in mice. This investigation identifies Abl as a potent regulator of MEC identity, and as a suppressor of oncogenic TGF-Beta signaling during breast cancer tumorigenesis. Importantly, our findings strongly caution against the use of pharmacological Abl inhibitors in developing and progressing mammary tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2009
- Accession Number
- ADA520037
Entities
People
- Tressa Allington
Organizations
- University of Colorado Boulder