A Biophysical-Computational Perspective of Breast Cancer Pathogenesis and Treatment Response
Abstract
The extracellular matrix (ECM) and its integrin receptors modulate breast tissue homeostasis and are altered significantly during breast tumor progression. We found that the mammary gland ECM stiffens prior to and in association with malignant transformation of the breast. We showed that ECM stiffening is mediated by elevated collagen deposition, cross-linking and linearization. We determined that collagen stiffening via cross linking in culture and in vivo promotes breast tumor invasion and can modulate mammary epithelial cell survival and therapy responsiveness. ECM stiffness modulates breast cell behavior by altering integrin-dependent signaling through ERK, PI3kinase and JNK and by regulating the levels and activity of the tumor suppressor PTEN. We identified lysyl oxidase as a key regulator of ECM cross linking and matrix stiffening in the malignant breast and found that inhibiting lysyl oxidase activity substantially inhibited tumor progression in vivo. More recently we were able to successfully build a computational model of the integrin-ECM-cell membrane/cytoskeletal interface and by so doing identified a novel molecular regulator of integrin signaling whose significance we are now exploring. Finally, and most importantly the clinical relevance of our findings is now being explored.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2008
- Accession Number
- ADA572697
Entities
People
- Valerie M Weaver
Organizations
- University of California, San Francisco