c-Met/HGF in triple negative breast cancer
Gaule, Patricia (2015) c-Met/HGF in triple negative breast cancer. PhD thesis, Dublin City University.
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Triple negative breast cancer (TNBC) is a subtype of breast cancer which is negative for the oestrogen receptor, progesterone receptor and lacks over-expression of HER2. The aim of this PhD was to examine c-Met and its ligand HGF as potential targets for TNBC. Expression of c-Met was higher in TNBC relative to other subtypes of BC. c-Met expression did not show a significant association with patient outcome (DFS/OS). We evaluated 3 c-Met/HGF selective inhibitors (CpdA, PRS110 and rilotumumab) in the panel of TNBC cell lines. Only CpdA showed moderate responses in proliferation assays. Cell lines were significantly more sensitive to c-Met inhibition by either CpdA or PRS110 in clonogenic assays. 3D growth assays were all significantly less sensitive to c-Met inhibition. Co-expression of c-Met and Src/p-Src (Y418) was detected in 86.6 /38.8 % respectively. No significant association was seen between clinico- pathological variables. Combined treatment with c-Met inhibitors and HGF, EGFR or Src inhibitors enhanced response in some cell lines suggesting a potential role in specific subsets of TNBC.
A dasatinib resistant and a cetuximab resistant TN cell line (231-DasB and MDA-MB-CR) showed increased sensitivity to CpdA compared to the parental cells. The parental cell lines show synergistic inhibition of growth with combination of CpdA and dasatinib or cetuximab.
We identified 7 receptor tyrosine kinases (FGFR1, FGFR3, VEGFR1, PDGFRβ, ROS1, TIE1 and EPHA5) which are associated with poor outcome (DFS/OS). Combined expression of FGFR3, EPHA5 and ROS1 shows significantly stronger association than the RTKs as single prognostic indicators. FGFR3 was associated with histological subtype and EPHA5 was significantly associated with increased age at diagnosis.
Based on our in vitro evaluation, targeting c-Met/HGF signalling does not appear to be a promising therapeutic strategy for TNBC. We identified FGFR3 and EPHA5 as potential targets which warrant further investigation in TNBC.
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