title: Matrix rigidity induces osteolytic gene expression of metastatic breast cancer cells.
abstract: Nearly 70% of breast cancer patients with advanced disease will develop bone metastases. Once established in bone, tumor cells produce factors that cause changes in normal bone remodeling, such as parathyroid hormone-related protein (PTHrP). While enhanced expression of PTHrP is known to stimulate osteoclasts to resorb bone, the environmental factors driving tumor cells to express PTHrP in the early stages of development of metastatic bone disease are unknown. In this study, we have shown that tumor cells known to metastasize to bone respond to 2D substrates with rigidities comparable to that of the bone microenvironment by increasing expression and production of PTHrP. The cellular response is regulated by Rho-dependent actomyosin contractility mediated by TGF-ß signaling. Inhibition of Rho-associated kinase (ROCK) using both pharmacological and genetic approaches decreased PTHrP expression. Furthermore, cells expressing a dominant negative form of the TGF-ß receptor did not respond to substrate rigidity, and inhibition of ROCK decreased PTHrP expression induced by exogenous TGF-ß. These observations suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis, which is especially important in metastatic cancer since many cancers (such as those of the breast and lung) preferentially metastasize to bone.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Nazanin S
authors.initials: NS
authors.lastname: Ruppender
authors.forename: Alyssa R
authors.initials: AR
authors.lastname: Merkel
authors.forename: T John
authors.initials: TJ
authors.lastname: Martin
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Mundy
authors.forename: Julie A
authors.initials: JA
authors.lastname: Sterling
authors.forename: Scott A
authors.initials: SA
authors.lastname: Guelcher
mesh_terms: D000465:Algorithms; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010014:Osteolysis / Q000235:genetics*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D044162:Parathyroid Hormone-Related Protein; D016212:Transforming Growth Factor beta; D054460:rho-Associated Kinases