Tissue Stiffness Enhances Malignant Transformation through Increased PI3 Kinase Signaling

KR LEVENTAL; L KASS; JT ERLER; P MRASS; AJ GIACCIA; W WENINGER; D GASSER; VM WEAVER

Washington, DC, USA

Congreso; The American Society of Cell Biology (ASCB, 47th Annual Meeting); 2007

The American Society of Cell Biology

Physical palpation has long been a means to detect tumor formation; however, the role of tissue mechanics in tumorigenesis is poorly understood. We are using MMTV-Her2/neu transgenic mice and organotypic mammary epithelial cell (MEC) three-dimensional (3D) tissue models to study how alterations in the physical properties of the extracellular matrix (ECM) could modulate mammary tumorigenesis. Using compression and shear analysis, we found that malignant transformation is preceded by and associated with a progressive increase in mammary gland stiffness. Because we found that gland stiffness, altered tissue morphology, and tumor invasiveness are functionally linked to increased collagen deposition, bundling, and lysyl oxidase (LOX) expression, we examined the relevance and molecular mechanisms whereby ECM stiffness might influence normal breast epithelia and breast tumor behavior. Concomitantly, 3D organotypic MEC studies illustrated that elevated tissue stiffness, through increased collagen crosslinking, synergistically promoted tumor invasion in cooperation with expression of an oncogene such as ErbB2. Consistently, pharmacological inhibition of LOX-mediated collagen crosslinking repressed mammary gland transformation in MMTV-Her2/neu mice. Finally, we determined that matrix stiffness enhances epidermal growth factor (EGF) receptor-dependent PI3 kinase activity and are currently investigating if matrix stiffness promotes transformation by altering EGFR-dependent PI3 kinase signaling and if so how.