Abstract
BackgroundPlatelet-derived growth factors (PDGFs) bind to two receptors, PDGFRα and PDGFRβ to mediate 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 cancer cells that have undergone epithelial to mesenchymal transition.MethodsPDGFR signaling was inhibited using Sunitinib malate, Imatinib mesylate 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.ResultsSunitinib and Regorafenib, but not Imatinib, were capable of significantly inhibiting the migration of both murine and human luminal-like and claudin-low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines. 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. None of the PDGFR inhibitors consistently regulated mammary tumor cell apoptosis.ConclusionSunitinib, 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.
Highlights
Platelet derived growth factors (PDGFs), as the name suggests, were originally purified from platelets [1,2,3,4]
We have previously shown that RJ348 cells have characteristics similar to human claudin-low breast cancer while RJ345 cells resemble human luminal breast cancer [26]
We have previously shown that RJ348 cells have elevated levels of PDGFRα and PDGFRβ compared to RJ345 cells and RNAi mediated knockdown of PDGFRs inhibited migration of RJ348 cells [25]
Summary
Platelet derived growth factors (PDGFs), as the name suggests, were originally purified from platelets [1,2,3,4]. 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. PDGFRs 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]. Platelet-derived growth factors (PDGFs) bind to two receptors, PDGFRα and PDGFRβ to mediate cell proliferation, migration and survival. Epithelial cells typically do not express high levels of PDGFRs, their expression has been reported to increase in breast cancer cells that have undergone epithelial to mesenchymal transition
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