Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer.
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 node-negative 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.
Ponzo
Marisa G
MG
Goodman Cancer Centre, McGill University, Montreal, QC, Canada H3A 1A3.
Lesurf
Robert
R
Petkiewicz
Stephanie
S
O'Malley
Frances P
FP
Pinnaduwage
Dushanthi
D
Andrulis
Irene L
IL
Bull
Shelley B
SB
Chughtai
Naila
N
Zuo
Dongmei
D
Souleimanova
Margarita
M
Germain
David
D
Omeroglu
Atilla
A
Cardiff
Robert D
RD
Hallett
Michael
M
Park
Morag
M
D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000032:analysis
D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D019859:Proto-Oncogene Proteins c-met