The Role of Notch Signaling Pathway in Breast Cancer Pathogenesis
Abstract
Constitutively active forms of Notch receptors have been shown to have oncogenic potential in several cell-types. Aberrant expression of Notch signaling pathway components has been detected in several human tumors, including breast cancer. Since Ras signaling is also activated in several breast cancers, I propose to study the potential interactions between Notch and Ras signaling in breast carcinogenesis. Initial observations revealed that coexpression of a constitutively active form of Notch1 in immortalized breast epithelial HMLE cells expressing low levels of oncogenic Ras rendered them fully transformed. These cells generated soft agar colonies in vitro, and tumors when injected subcutaneously in nude mice. Further characterization of the Notch-Ras pathway interaction revealed that nuclear localization of Notch1 is essential for this cooperation. Dissection of Ras-pathways using the Ras-effector loop mutants revealed that compared to G37 and C40, that activate Ral-GEF and PI3K, respectively, the 535 mutant, which preferentially activates Raf/MAPK pathway, formed efficient colonies with activated Notch1. Interestingly, I found that expression of activated Notch1 rendered the HMLE-low Ras cells highly spindly and fibroblastic - characteristics of epithelial-to-mesenchyme transition (EMT) associated with tumor invasion and metastasis. Very recent reports have indeed demonstrated a role for Notch signaling in EMT associated with normal development and cancers. Accordingly, I investigated the role of Notch signaling in the EMT phenotype of breast cancer cells. I found that inhibition of Notch signaling, using presenilin inhibitor, caused the highly metastatic SUM1315 breast cancer cells to revert to an epithelial phenotype, thereby suggesting that Notch signaling may play an important role in mediating/maintaining the EMT phenotype of breast cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA429183
Entities
People
- Annapoorni Rangarajan
Organizations
- Whitehead Institute