Breast cancer is known to have a predilection for metastasizing to bone where it occurs in over 70% of patients with advanced disease. While several factors have been described as important regulators of tumor-induced bone destruction,  parathyroid hormone related protein (PTHrP) is perhaps the best described and is well established to be expressed clinically at high levels in bone metastases compared to the level of expression in soft tissue metastases or primary tumors.  This increase in bone resorption results in release of TGF-b from the bone matrix that continues to drive the expression of PTHrP by the tumor cells. While the mechanisms of TGF-� regulation of PTHrP expression in tumor-induced bone disease have been studied extensively, it is still unclear why PTHrP expression is higher in bone.  One of the primary mechanisms regulating the cellular response to rigidity is cross-talk between integrins and growth factor receptors, which has been shown to mediate tumor malignancy and invasiveness.  For example, TGF�RII interacts physically with avb3 integrin to enhance TGF-b-mediated stimulation of MAP-kinases (MAPKs) and Smad2/3-mediated gene transcription in mammary epithelial cells (MECs) during epithelial-mesenchymal transition (EMT).  Integrin avb3 in tumor cells regulates the early stages of skeletal metastasis in both breast and prostate cancer, and inhibition of avb3 in osteoclasts reduces bone loss in models of osteolytic skeletal metastases, where avb3 integrin is required by osteoclasts to resorb the bone matrix. In the present study, we hypothesized that rigid matrices induce increased clustering of avb3 integrin and TGFbRII to initiate signaling by SFKs, resulting in the expression of osteolytic genes in breast cancer cells via ROCK. We designed hydrogel, polyurethane (PUR), and Pyrex� glass 2D monoculture systems to mimic the viscoelastic properties of breast tissue, the basement membrane, and mineralized bone in vitro.

Effects of matrix rigidity on osteolytic gene expression in tumor cells

244th National Meeting (2012)

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