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|Title:||Tyrosine phosphorylation of transcriptional coactivator WW-domain binding protein 2 regulates estrogen receptor α function in breast cancer via the Wnt pathway||Authors:||Lim, S.K.
|Issue Date:||Sep-2011||Citation:||Lim, S.K., Orhant-Prioux, M., Toy, W., Tan, K.Y., Lim, Y.P. (2011-09). Tyrosine phosphorylation of transcriptional coactivator WW-domain binding protein 2 regulates estrogen receptor α function in breast cancer via the Wnt pathway. FASEB Journal 25 (9) : 3004-3018. ScholarBank@NUS Repository. https://doi.org/10.1096/fj.10-169136||Abstract:||WW-binding protein 2 (WBP2) has been demonstrated in different studies to be a tyrosine kinase substrate, to activate estrogen receptor α (ERα)/progesterone receptor (PR) transcription, and to play a role in breast cancer. However, the role of WBP2 tyrosine phosphorylation in regulating ERα function and breast cancer biology is unknown. Here, we established WBP2 as a tyrosine phosphorylation target of estrogen signaling via EGFR crosstalk. Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases. We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα. Compared to vector control, overexpression of WBP2 and its phospho-mimic mutant in MCF7 cells resulted in larger tumors in mice, induced loss of cell-cell adhesion, and enhanced cell proliferation, anchorageindependent growth, migration, and invasion in both estrogen-dependent and -independent manners, events of which could be substantially abolished by overexpression of the phosphorylation-defective mutant. Hormone independence of cells expressing WBP2 phospho-mimic mutant was associated with heightened ERα and Wnt reporter activities. Wnt/β-catenin inhibitor FH535 blocked phospho-WBP2-mediated cancer cell growth more pronouncedly than tamoxifen and fulvestrant, in part by reducing the expression of ERα. Wnt pathway is likely to be a critical component in WBP2-mediated breast cancer biology. © FASEB.||Source Title:||FASEB Journal||URI:||http://scholarbank.nus.edu.sg/handle/10635/108587||ISSN:||08926638||DOI:||10.1096/fj.10-169136|
|Appears in Collections:||Staff Publications|
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