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Molecular & Cellular Proteomics 6:2072-2087, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Differential Expression of Novel Tyrosine Kinase Substrates during Breast Cancer Development ^*,S

Yunhao Chen^,, Lee-Yee Choong^,, Qingsong Lin^¶, Robin Philp^||, Chee-Hong Wong^**, Boon-Keong Ang^**, Yee-Ling Tan, Marie-Chiew-Shia Loh^**, Choy-Leong Hew^¶, Nilesh Shah, Brian J. Druker, Poh-Kuan Chong and Yoon-Pin Lim^,¶,**,

From the Oncology Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore, ^¶ Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore, ^|| Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore, Howard Hughes Medical Institute, Oregon Health and Science University, Portland, Oregon 97239, and ^** Bioinformatics Institute, Agency for Science, Technology and Research, Singapore 138671, Singapore

To identify novel tyrosine kinase substrates that have never been implicated in cancer, we studied the phosphoproteomic changes in the MCF10AT model of breast cancer progression using a combination of phosphotyrosyl affinity enrichment, iTRAQ^TM technology, and LC-MS/MS. Using complementary MALDI- and ESI-based mass spectrometry, 57 unique proteins comprising tyrosine kinases, phosphatases, and other signaling proteins were detected to undergo differential phosphorylation during disease progression. Seven of these proteins (SPAG9, Toll-interacting protein (TOLLIP), WBP2, NSFL1C, SLC4A7, CYFIP1, and RPS2) were validated to be novel tyrosine kinase substrates. SPAG9, TOLLIP, WBP2, and NSFL1C were further proven to be authentic targets of epidermal growth factor signaling and Iressa (gefitinib). A closer examination revealed that the expression of SLC4A7, a bicarbonate transporter, was down-regulated in 64% of the 25 matched normal and tumor clinical samples. The expression of TOLLIP in clinical breast cancers was heterogeneous with 25% showing higher expression in tumor compared with normal tissues and 35% showing the reverse trend. Preliminary studies on SPAG9, on the other hand, did not show differential expression between normal and diseased states. This is the first time SLC4A7 and TOLLIP have been discovered as novel tyrosine kinase substrates that are also associated with human cancer development. Future molecular and functional studies will provide novel insights into the roles of TOLLIP and SLC4A7 in the molecular etiology of breast cancer.

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