title: Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway.
abstract: Inflammatory breast cancer (IBC) accounts for a small fraction but aggressive form of epithelial breast cancer. Although the role of thrombin in cancer is beginning to be unfolded, its impact on the biology of IBC remains unknown. The purpose of this study was to establish the role of thrombin on the invasiveness of IBC cells. The IBC SUM149 cell line was treated with thrombin in the absence or presence of the epidermal growth factor receptor (EGFR) inhibitor erlotinib and protease-activated receptor 1 (PAR1) inhibitor. The effects of pharmacological inhibitors on the ability of thrombin to stimulate the growth rate and invasiveness were examined. We found that the inhibition of putative cellular targets of thrombin action suppresses both the growth and invasiveness of SUM149 cells in a concentration-dependent manner. In addition, thrombin-mediated increased invasion of SUM149 cells was routed through EGFR phosphorylation, and in turn, stimulation of the p21-activated kinase (Pak1) activity in a EGFR-sensitive manner. Interestingly, thrombin-mediated activation of the Pak1 pathway stimulation was blocked by erlotinib and PAR1 inhibitor. For proof-of-principle studies, we found immunohistochemical evidence of Pak1 activation as well as expression of PAR1 in IBC. Thrombin utilizes EGFR to relay signals promoting SUM149 cell growth and invasion via the Pak1 pathway. The study provides the rationale for future therapeutic approaches in mitigating the invasive nature of IBC by targeting Pak1 and/or EGFR.
authors.affiliation: Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, District of Columbia 20037, USA.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Tri M
authors.initials: TM
authors.lastname: Bui-Nguyen
authors.forename: Reddy S
authors.initials: RS
authors.lastname: Divijendra Natha
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Schwartz
authors.forename: Paul
authors.initials: P
authors.lastname: Levine
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D044463:Receptor, PAR-1; D066246:ErbB Receptors; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D013917:Thrombin