title: Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.
abstract: Triple-negative breast cancer (TNBC) accounts for ∼20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Met(mt)) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Met(mt) mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Met(mt), significantly increased tumor penetrance over Met(mt) or Trp53 loss alone. Unlike Met(mt) tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Met(mt) tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-to-mesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-low morphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Knight
authors.forename: Robert
authors.initials: R
authors.lastname: Lesurf
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Dushanthi
authors.initials: D
authors.lastname: Pinnaduwage
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Davis
authors.forename: Sadiq M I
authors.initials: SM
authors.lastname: Saleh
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zuo
authors.forename: Monica A
authors.initials: MA
authors.lastname: Naujokas
authors.forename: Naila
authors.initials: N
authors.lastname: Chughtai
authors.forename: Jason I
authors.initials: JI
authors.lastname: Herschkowitz
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Mulligan
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Jeff P
authors.initials: JP
authors.lastname: Gregg
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hallett
authors.forename: Morag
authors.initials: M
authors.lastname: Park
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D057167:Claudins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: D057167:Claudins; D016159:Tumor Suppressor Protein p53; D019859:Proto-Oncogene Proteins c-met