title: Hic-5 remodeling of the stromal matrix promotes breast tumor progression.
abstract: The remodeling of the stromal extracellular matrix (ECM) has a crucial, but incompletely understood role during tumor progression and metastasis. Hic-5, a focal adhesion scaffold protein, has previously been implicated in tumor cell invasion, proliferation and metastasis. To investigate the role of Hic-5 in breast tumor progression in vivo, Hic-5-/-mice were generated and crossed with the Mouse Mammary Tumor Virus-Polyoma Middle T-Antigen mouse. Tumors from the Hic-5-/-;PyMT mice exhibited increased latency and reduced growth, with fewer lung metastases, as compared with Hic-5+/-;PyMT mice. Immunohistochemical analysis showed that Hic-5 is primarily expressed in the cancer-associated fibroblasts (CAFs). Further analysis revealed that the Hic-5-/-;PyMT tumor stroma contains fewer CAFs and exhibits reduced ECM deposition. The remodeling of the stromal matrix by CAFs has been shown to increase tumor rigidity to indirectly regulate FAK Y397 phosphorylation in tumor cells to promote their growth and invasion. Accordingly, the Hic-5-/-;PyMT tumor cells exhibited a reduction in FAK Y397 phosphorylation. Isolated Hic-5-/-;PyMT CAFs were defective in stress fiber organization and exhibited reduced contractility. These cells also failed to efficiently deposit and organize the ECM in two and three dimensions. This, in turn, impacted three-dimensional MDA-MB-231 tumor cell migration behavior. Thus, using a new knockout mouse model, we have identified Hic-5 expression in CAFs as a key requirement for deposition and remodeling of the stromal ECM to promote non-cell autonomous breast tumor progression.
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Goreczny
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Ouderkirk-Pecone
authors.affiliation: Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Olson
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY, USA.
authors.forename: M
authors.identifier: 0000-0002-7008-9069
authors.initials: M
authors.lastname: Krendel
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Turner
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000235:genetics / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060588:LIM Domain Proteins / Q000096:biosynthesis / Q000235:genetics*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000472:pathogenicity; D051379:Mice; D018345:Mice, Knockout; D017154:Stromal Cells / Q000473:pathology
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C090090:Tgfb1i1 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse