title: The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis.
abstract: BACKGROUND
  The tumor microenvironment has complex effects in cancer pathophysiology that are not fully understood. Most cancer therapies are directed against malignant cells specifically, leaving pro-malignant signals from the microenvironment unaddressed. Defining specific mechanisms by which the tumor microenvironment contributes to breast cancer metastasis may lead to new therapeutic approaches against advanced breast cancer.
  
  
  METHODS
  We use a novel method for manipulating three-dimensional mixed cell co-cultures, along with studies in mouse xenograft models of human breast cancer and a histologic study of human breast cancer samples, to investigate how breast cancer-associated fibroblasts affect the malignant behaviors of breast cancer cells.
  
  
  RESULTS
  Altering fibroblast Tiam1 expression induces changes in invasion, migration, epithelial-mesenchymal transition, and cancer stem cell characteristics in associated breast cancer cells. These changes are both dependent on fibroblast secretion of osteopontin and also long-lasting even after cancer cell dissociation from the fibroblasts, indicating a novel Tiam1-osteopontin pathway in breast cancer-associated fibroblasts. Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis. Moreover, fibroblast expression patterns of Tiam1 and osteopontin in human breast cancers show converse changes correlating with invasion, supporting the hypothesis that this pathway in tumor-associated fibroblasts regulates breast cancer invasiveness in human disease and is thus clinically relevant.
  
  
  CONCLUSIONS
  These findings suggest a new therapeutic paradigm for preventing breast cancer metastasis. Pro-malignant signals from the tumor microenvironment with long-lasting effects on associated cancer cells may perpetuate the metastatic potential of developing cancers. Inhibition of these microenvironment signals represents a new therapeutic strategy against cancer metastasis that enables targeting of stromal cells with less genetic plasticity than associated cancer cells and opens new avenues for investigation of novel therapeutic targets and agents.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 75 Kneeland Street, Boston, MA, 02111, USA. kxu@tuftsmedicalcenter.org.
authors.forename: Kun
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Pathology, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. xtian1@partners.org.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Tian
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 75 Kneeland Street, Boston, MA, 02111, USA. suyoung@montefiore.org.|Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. suyoung@montefiore.org.
authors.forename: Sun Y
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. movassag@mit.edu.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Movassaghi
authors.affiliation: Department of Pathology, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. snaber@tuftsmedicalcenter.org.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Naber
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 75 Kneeland Street, Boston, MA, 02111, USA. charlotte.kuperwasser@tufts.edu.|Developmental, Molecular, and Chemical Biology Department, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA. charlotte.kuperwasser@tufts.edu.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 75 Kneeland Street, Boston, MA, 02111, USA. rbuchsbaum@tuftsmedicalcenter.org.|Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. rbuchsbaum@tuftsmedicalcenter.org.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Buchsbaum
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D017154:Stromal Cells / Q000473:pathology; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D059016:Tumor Microenvironment / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D053495:Osteopontin
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