Elevated MET receptor tyrosine kinase correlates with poor outcome in breast cancer, yet the reasons for this are poorly understood. We thus generated a transgenic mouse model targeting expression of an oncogenic Met receptor (Met mt ) to the mammary epithelium. We show that Met mt induces mammary tumors with multiple phenotypes. These reflect tumor subtypes with gene expression and immunostaining profiles sharing similarities to human basal and luminal breast cancers. Within the basal subtype, Met mt induces tumors with signatures of WNT and epithelial to mesenchymal transition (EMT). Among human breast cancers, MET is primarily elevated in basal and ERBB2-positive subtypes with poor prognosis, and we show that MET, together with EMT marker, SNAIL, are highly predictive of poor prognosis in lymph nodenegative patients. By generating a unique mouse model in which the Met receptor tyrosine kinase is expressed in the mammary epithelium, along with the examination of MET expression in human breast cancer, we have established a specific link between MET and basal breast cancer. This work identifies basal breast cancers and, additionally, poor-outcome breast cancers, as those that may benefit from anti-MET receptor therapies.gene expression profiling ͉ mouse models ͉ epithelial to mesenchymal transition B reast cancer is a heterogeneous disease that comprises distinct biological entities that are correlated with diverse clinical outcomes and responses to treatment. Gene expression profiling and molecular pathology have revealed that breast cancers naturally divide into the luminal, ERBB2-positive, and basal-like subtypes (1, 2). These subtypes were named to reflect gene expression patterns of the 2 principal cell types of the differentiated breast, luminal epithelial cells lining the duct and lobule, and myoepithelial cells that form a single layer surrounding the luminal cells. The luminal subtype comprises ϳ60% of breast cancers, is estrogen receptor (ESR1)-positive, and expresses ESR1-responsive genes and luminal markers such as keratin 8/18. Up to 25% of breast cancers are identified with overexpression/amplification of the ERBB2 receptor tyrosine kinase, and these tumors are generally ESR1/ progesterone receptor (PGR)-negative. The basal group is characterized as ESR1/PGR/ERBB2-negative and is frequently positive for basal keratins 5/6 (3, 4). Breast cancers within the luminal subtype receive antiestrogen therapies and tend to have a good prognosis. Because of the lack of treatment options, patients within the basal subtype historically have a poor prognosis (1). Hence, an understanding of the signaling pathways active in these tumors is crucial for the generation of targeted therapies.The MET receptor tyrosine kinase, which is the receptor for hepatocyte growth factor/scatter factor (HGF/SF), is expressed at elevated levels in 15-20% of human breast cancers (5), and is a prognostic factor for poor outcome (6, 7). High levels of the MET receptor ligand HGF/SF in the serum of breast cancer patients is also correl...
Activation of the hepatocyte growth factor receptor Met induces a morphogenic response and stimulates the formation of branching tubules by Madin-Darby canine kidney (MDCK) epithelial cells in three-dimensional cultures. A constitutively activated ErbB2/Neu receptor, NeuNT, promotes a similar invasive morphogenic program in MDCK cells. Because both receptors are expressed in breast epithelia, are associated with poor prognosis, and hepatocyte growth factor (HGF) is expressed in stroma, we examined the consequence of cooperation between these signals. We show that HGF disrupts NeuNT-induced epithelial morphogenesis, stimulating the breakdown of cell-cell junctions, dispersal, and invasion of single cells. This correlates with a decrease in junctional proteins claudin-1 and E-cadherin, in addition to the internalization of the tight junction protein ZO-1. HGF-induced invasion of NT-expressing cells is abrogated by pretreatment with a pharmacological inhibitor of the mitogen-activated protein kinase kinase (MEK) pathway, which restores E-cadherin and ZO-1 at cell-cell junctions, establishing the involvement of MEK-dependent pathways in this process. These results demonstrate that physiological signals downstream from the HGF/Met receptor synergize with ErbB2/Neu to enhance the malignant phenotype, promoting the breakdown of cell-cell junctions and enhanced cell invasion. This is particularly important for cancers where ErbB2/Neu is overexpressed and HGF is a physiological growth factor found in the stroma.
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