C-Met is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream pathways with diverse cellular functions that are important in organ development and cancer progression. Anomalous c-Met signalling has been described in a variety of cancer types, and the receptor is regarded as a novel therapeutic target. In breast cancer there is a need to develop new treatments, particularly for the aggressive subtypes such as triple-negative and basal-like cancer, which currently lack targeted therapy. Over the last two decades, much has been learnt about the functional role of c-Met signalling in different models of breast development and cancer. This work has been complemented by clinical studies, establishing the prognostic significance of c-Met in tissue samples of breast cancer. While the clinical trials of anti-c-Met therapy in advanced breast cancer progress, there is a need to review the existing evidence so that the potential of these treatments can be better appreciated. The aim of this article is to examine the role of HGF/c-Met signalling in in vitro and in vivo models of breast cancer, to describe the mechanisms of aberrant c-Met signalling in human tissues, and to give a brief overview of the anti-c-Met therapies currently being evaluated in breast cancer patients. We will show that the HGF/c-Met pathway is associated with breast cancer progression and suggest that there is a firm basis for continued development of anti-c-Met treatment, particularly for patients with basal-like and triple-negative breast cancer.

C-Met, the receptor of hepatocyte growth factor (HGF), through overexpression or mutation, is a major protooncogene that provides an attractive molecular target for cancer therapy. HGF/c-Met–induced tumorigenesis is dependent, in part, on the transcription factor and oncogene signal transducer and activator of transcription 3 (STAT3), which is believed to be activated by the receptor at the plasma membrane and then to travel to the nucleus where it acts. We demonstrate that although the robust signal to STAT3 elicited from the cytokine oncostatin-M does indeed support this mechanism of STAT3 action, for the weaker STAT3 signal emanating from c-Met, the activated receptor itself needs to be delivered to a perinuclear endosomal compartment to sustain phosphorylated STAT3 in the nucleus. This is signal specific because c-Met–induced extracellular signal-regulated kinase nuclear accumulation does not require receptor trafficking to the perinuclear compartment. This response is triggered from peripheral endosomes. Thus, control of growth factor receptor traffic determines the nature of the signal output, providing novel opportunities for intervention.

The growth factor/receptor pair HGF/c‐Met exerts control on proliferation, morphogenesis and motility, and through overexpression and mutation is implicated in cancer. Here we have investigated the relationship between receptor signalling and traffic, and its control by specific PKC isotypes. It is shown that c‐Met signalling to the ERK cascade occurs within endosomal compartments and that it is in this compartment that PKCε specifically exerts its control on the pathway with the consequent accumulation of ERK in focal complexes. These events are clearly separated from the subsequent microtubule‐dependent sorting of c‐Met to its perinuclear destination, which is shown to be under the control of PKCα. Thus while it is shown that traffic to endosomes is essential for HGF/c‐Met to trigger an ERK response, the subsequent traffic and signalling of c‐Met controlled by these two PKC isotypes are unconnected events. The dynamic properties conferred by the PKCε control are shown to be essential for a normal HGF‐dependent migratory response. Thus PKCs are shown to control both receptor traffic and signal traffic to relay HGF/c‐Met responses.

Chemotherapy remains the mainstay of treatment in the majority of solid and haematological malignancies. Resistance to cytotoxic chemotherapy is a major clinical problem and substantial research is ongoing into potential methods of overcoming this resistance. One major target, the receptor tyrosine kinase MET, has generated increasing interest with multiple clinical trials in progress. Overexpression of MET is frequently observed in a range of different cancers and is associated with poor prognosis. Studies have shown that MET promotes resistance to targeted therapies, including those targeting EGFR, BRAF and MEK. More recently, several reports suggest that MET also contributes to cytotoxic chemotherapy resistance. Here we review the preclinical evidence of MET’s role in chemotherapy resistance, the mechanisms by which this resistance is mediated and the translational relevance of MET inhibitor therapy for patients with chemotherapy resistant disease.

Down's syndrome is caused by the presence of an extra copy of chromosome 21 (a state known as trisomy), and it is known that the growth of certain tumours is reduced in this genetic disorder. A study of a mouse model of Down's syndrome points to an antitumour mechanism, the inhibition of tumour angiogenesis by the overexpression of four genes, two putative anti-angiogenic genes (ADAMTS1 and ERG) and two novel endothelial cell-specific genes not previously linked with angiogenesis (JAM-B and PTTG1IP). Down's syndrome is caused by trisomy of chromosome 21, and it is known that the growth of certain tumours is reduced in this genetic disorder. Using a mouse model of Down's syndrome, several individual genes on chromosome 21 are now being proposed to mediate the effect on tumour growth and angiogenesis. Down’s syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours1,2. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes4 (a previously known suppressor of angiogenesis5,6) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS7 to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS18,9and ERG10) and novel endothelial cell-specific genes11, never previously shown to be involved in angiogenesis (JAM-B12 and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.