1 Department of Biomedical Sciences, penthouse stuttgart Ontario Veterinary College, University of G

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1 Department of Biomedical Sciences, penthouse stuttgart Ontario Veterinary College, University of Guelph, Guelph N1G2W1, ON, Canada
The electronic version of this article is the complete one and can be found online at: http://www.cancerci.com/content/14/1/89 Received: 26 March 2014 Accepted: 29 August 2014 Published: 5 September 2014
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Platelet-derived growth penthouse stuttgart factors (PDGFs) bind to two receptors, PDGFRα and PDGFRβ to mediate penthouse stuttgart cell proliferation, migration and survival. Although epithelial cells typically do not express high levels of PDGFRs, their expression has been reported to increase in breast penthouse stuttgart cancer cells that have undergone epithelial to mesenchymal transition. Methods penthouse stuttgart
PDGFR signaling was inhibited using Sunitinib malate, Imatinib penthouse stuttgart mesylate penthouse stuttgart or Regorafenib in murine and human luminal-like and claudin-low mammary tumor cell lines or Masitinib in only the human cell lines. A scratch wound assay was used to assess tumor cell migration while immunofluorescence for phosphorylated histone H3 or cleaved caspase 3 was used to determine tumor cell proliferation and apoptosis, respectively. Results
Sunitinib and Regorafenib, but not Imatinib, were capable of significantly inhibiting the migration of both murine penthouse stuttgart and human luminal-like and claudin-low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines. penthouse stuttgart Sunitinib but not Regorafenib or Imatinib also significantly suppressed tumor cell proliferation in all four cell lines tested while Masitinib had no significant effect on human breast cancer cell proliferation. penthouse stuttgart None of the PDGFR inhibitors consistently regulated mammary tumor cell apoptosis. Conclusion
Sunitinib, Regorafenib and Masitinib may prove clinically useful in inhibiting breast cancer cell migration and metastasis while only Sunitinib (and possibly Regorafenib in some breast cancer subtypes) is effective at inhibiting both migration and proliferation of breast cancer cells. 1 Introduction
Platelet derived growth factors (PDGFs), as the name suggests, were originally purified from platelets [ 1 ] [ 4 ]. PDGFs form homodimers consisting of A-, B-, C- and D-polypeptides or heterodimers consisting of A and B polypeptides. These ligands induce signaling by binding to one of two PDGFR receptor isoforms, PDGFRα and PDGFRβ. PDGFRα binds all members of the PDGF dimers other than D-polypeptides while PDGFRβ bind the B- and D-polypeptides [ 5 ]. PDGFRs penthouse stuttgart are tyrosine kinase receptors and ligand binding induces receptor dimerization and intracellular signaling including activation of PLCγ, Src, SHP-2, RasGAP, PI3-kinase and STAT proteins [ 5 ]. These signaling penthouse stuttgart pathways regulate cell proliferation, survival, chemotaxis and differentiation.
PDGFRs are typically not expressed in normal epithelial penthouse stuttgart cells but are expressed in fibroblasts and smooth muscle cells [ 6 ] where these receptors regulate physiologic processes such as wound healing, inflammation and angiogenesis [ 7 ]. Tumors associated with enhanced PDGFR signaling include sarcomas, penthouse stuttgart gastrointestinal stromal tumors and several types of leukemias [ 8 ].
With respect to breast cancer, less is known about the importance of PDGFs or PDGFRs. Studies have shown that PDGF-D is upregulated in invasive breast cancer while PDGF-BB is found at higher penthouse stuttgart levels in patients with breast cancer compared to those with benign breast disease and the expression PDGFRs is a predictor of poor prognosis [ 9 ] [ 11 ]. Additionally, more recent research has found that PDGF signaling is elevated in breast cancer cells that have become resistant to endocrine therapy [ 12 ], [ 13 ]. Another potential role of PGDFR signaling in breast cancer is during epithelial to mesenchymal transistion (EMT). EMT is a process whereby epithelial cells acquire a more mesenchymal phenotype and gene expression profile and EMT has been implicated in more aggressive/metastatic breast cancers [ 14 ] [ 17 ].
A number of agents capable of inhibiting PDGFR signaling have been developed including Sunitinib malate (Sutent), BAY 73 4506 (Regorafenib) penthouse stuttgart and Imatinib mesylate (