Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer

Abstract

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...

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

“…We report here a higher expression of ST8SIA1 in the basal subtype of breast tumors compared with others. Interestingly, a similar pattern was found for MET, in accordance with previous reports (38,45,46). c-Met is also associated with poor clinical outcome and considered as a possible marker for earlier recurrence and shorter survival in breast cancer patients (47)(48)(49).…”

PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition

“…We also showed that both PYK2 and phospho-STAT3 positively regulate EMT in several mammary carcinoma cell lines (Figs 1c,d, 3d and 7a,b). Importantly, c-Met is also associated with EMT signature in triple-negative breast cancer 51,52 and plays a central role in breast cancer progression and metastasis 53 . Furthermore, previous studies suggest that the activation of STAT3 downstream of c-Met is crucial for cell invasion 54 , transformation and tumorigenesis 55 .…”

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

“…S3A). Next, a Cre-inducible allele of the MET receptor tyrosine kinase, which is associated with EMT and therapy resistance (18,19), and expressed at high levels in breast cancer (20)(21)(22), was introduced in KB1P-Col1a1 ESC clone A2.1 to produce K14cre;Brca1 F/F ; Trp53 F/F ;Col1a1 inv-CAG-Met-Luc (KB1P-MET) ESCs (Fig. S3B).…”