Abstract
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.
Highlights
Gene expression profiling has revealed five breast cancer subtypes that differ in their prognosis and therapeutic responsiveness: luminal A and B [both estrogen receptor (ER)–positive], erbB2, basal and normal-like (ER-negative; ref. 1) subtypes
We identified 544 sites of tyrosine phosphorylation in peptide sequences derived from 295 nonredundant proteins (Supplementary Tables S2 and S3)
We have used a global phosphoproteomic approach to characterize phosphotyrosine-based signaling networks in breast cancer cells of contrasting phenotypes, providing a rich information resource that complements those describing genomic and transcriptomic alterations [11, 31]. This approach has identified that Src family kinase (SFK) govern a signaling network in basal breast cancer cells that extends downstream to canonical SFK substrates regulating cell adhesion and migration and upstream to specific receptor tyrosine kinases (RTK), and that Lyn is a key component of this network (Fig. 5)
Summary
Gene expression profiling has revealed five breast cancer subtypes that differ in their prognosis and therapeutic responsiveness: luminal A and B [both estrogen receptor (ER)–positive], erbB2 ( known as HER2), basal and normal-like (ER-negative; ref. 1) subtypes. Gene expression profiling has revealed five breast cancer subtypes that differ in their prognosis and therapeutic responsiveness: luminal A and B [both estrogen receptor (ER)–positive], erbB2 ( known as HER2), basal and normal-like The basal subtype accounts for 10% to 27% of breast cancer cases, depending on the patient population [2, 3]. The common absence of ER, progesterone receptor (PR) and Authors' Affiliations: 1Cancer Research Program, Garvan Institute of Medical Research; 2St. Vincent's Hospital Clinical School and 3Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, New South Wales, Australia; and 4Division of Pathology and Edinburgh Breakthrough Research Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia. Phone: 61-2-9295-8333; Fax: 61-2-9295-8321; E-mail: r.daly@garvan. org.au
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