title: EMT Transition Alters Interstitial Fluid Flow-Induced Signaling in ERBB2-Positive Breast Cancer Cells.
abstract: A variety of biophysical forces are altered in the tumor microenvironment (TME) and these forces can influence cancer progression. One such force is interstitial fluid flow (IFF)-the movement of fluid through the tissue matrix. IFF was previously shown to induce invasion of cancer cells, but the activated signaling cascades remain poorly understood. Here, it is demonstrated that IFF induces invasion of ERBB2/HER2-expressing breast cancer cells via activation of phosphoinositide-3-kinase (PI3K). In constitutively activate ERBB2-expressing cells that have undergone epithelial-to-mesenchymal transition (EMT), IFF-mediated invasion requires the chemokine receptor CXCR4, a gradient of its ligand CXCL12, and activity of the PI3K catalytic subunits p110α and β. In wild-type ERBB2-expressing cells, IFF-mediated invasion is chemokine receptor-independent and requires only p110α activation. To test whether cells undergoing EMT alter their signaling response to IFF, TGFβ1 was used to induce EMT in wild-type ERBB2-expressing cells, resulting in IFF-induced invasion dependent on CXCR4 and p110β.
  
  
  CONCLUSIONS
  This study identifies a novel signaling mechanism for interstitial flow-induced invasion of ERBB2-expressing breast cancer cells, one that depends on EMT and acts through a CXCR4-PI3K pathway. These findings suggest that the response of cancer cells to interstitial flow depends on EMT status and malignancy.
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Alimatou M
authors.initials: AM
authors.lastname: Tchafa
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Mi
authors.initials: M
authors.lastname: Ta
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania. adrian.c.shieh@drexel.edu Mauricio.Reginato@drexelmed.edu.
authors.forename: Mauricio J
authors.initials: MJ
authors.lastname: Reginato
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania. adrian.c.shieh@drexel.edu Mauricio.Reginato@drexelmed.edu.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Shieh
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D045604:Extracellular Fluid / Q000502:physiology*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D059016:Tumor Microenvironment
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta; C527276:CXCR4 protein, human; C508053:ERBB2 protein, human