Tyrosine phosphorylation profiling reveals the signaling network characteristics of Basal breast cancer cells.
To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry-based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup.
Hochgräfe
Falko
F
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital Clinical School and Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, New South Wales, Australia.
Zhang
Luxi
L
O'Toole
Sandra A
SA
Browne
Brigid C
BC
Pinese
Mark
M
Porta Cubas
Ana
A
Lehrbach
Gillian M
GM
Croucher
David R
DR
Rickwood
Danny
D
Boulghourjian
Alice
A
Shearer
Robert
R
Nair
Radhika
R
Swarbrick
Alexander
A
Faratian
Dana
D
Mullen
Peter
P
Harrison
David J
DJ
Biankin
Andrew V
AV
Sutherland
Robert L
RL
Raftery
Mark J
MJ
Daly
Roger J
RJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018295:Neoplasms, Basal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000145:classification / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040901:Proteomics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D014443:Tyrosine; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051416:Focal Adhesion Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases