A Biophysico-Computational Perspective of Breast Cancer Pathogenesis and Treatment Response
Abstract
Apoptosis resistance regulates breast transformation and treatment responsiveness, yet the mechanism(s) enhancing breast cancer cell survival remain unclear. We showed that malignant transformation is associated with increased matrix deposition, cross-linking and reorganization that correlate with a progressive stiffening of the gland. Organotypic culture experiments demonstrated that stiffening the extracellular matrix (ECM) destabilizes cell-cell junctions, enhances integrin-dependent adhesions, alters survival, and compromises mammary morphogenesis and the integrity of differentiated mammary tissues. Matrix force also promotes oncogene-mediated invasion and malignant transformation of mammary epithelial cells (MECs) in culture and in vivo, by inducing cell-generated force and RhoGTPase, ERK, PI3 kinase and JNK signaling. Consistently, deterministic modeling predicted that chronically-activated ERK drives cell transformation, and while the model does not incorporate adhesion-dependent force, we did find that pre-malignant MECs with genetically modified integrins have elevated ERK signaling, and are invasion in culture and tumorigenic in vivo. We are now testing whether inhibiting ECM stiffening or changing integrin signaling will either prevent or promote malignant transformation in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA474715
Entities
People
- Valerie M Weaver
Organizations
- University of Pennsylvania