Qinghua Liu1,2, Lixin He1, Siqi Li1,3, Fengyan Li4, Guangzheng Deng3, Xinjian Huang1,3, Muwen Yang1, Yunyun Xiao1, Xiangfu Chen1, Ying Ouyang1, Jinxin Chen1, Xuxia Wu1, Xi Wang1,3, Libing Song1, Chuyong Lin5. 1. State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. 2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China. 3. Department of Breast Surgery, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China. 4. Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China. 5. State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. Linchuyong999@gmail.com.
Abstract
BACKGROUND: HOMER family scaffolding proteins (HOMER1-3) play critical roles in the development and progression of human disease by regulating the assembly of signal transduction complexes in response to extrinsic stimuli. However, the role of HOMER protein in breast cancer remains unclear. METHODS: HOMER3 expression was examined by immunohistochemistry in breast cancer patient specimens, and its significance in prognosis was assessed by Kaplan-Meier survival analysis. The effects of HOMER3 in growth factor-induced β-Catenin activation were analyzed by assays such as TOP/FOP flash reporter, tyrosine phosphorylation assay and reciprocal immunoprecipitation (IP) assay. Role of HOMER3 in breast cancer metastasis was determined by cell function assays and mice tumor models. RESULTS: Herein, we find that, among the three HOMER proteins, HOMER3 is selectively overexpressed in the most aggressive triple negative breast cancer (TNBC) subtype, and significantly correlates with earlier tumor metastasis and shorter patient survival. Mechanismly, HOMER3 interacts with both c-Src and β-Catenin, thus providing a scaffolding platform to facilitate c-Src-induced β-Catenin tyrosine phosphorylation under growth factor stimulation. HOMER3 promotes β-Catenin nuclear translocation and activation, and this axis is clinically relevant. HOMER3 promotes and is essential for EGF-induced aggressiveness and metastasis of TNBC cells both in vitro and in vivo. CONCLUSION: These findings identify a novel role of HOMER3 in the transduction of growth factor-mediated β-Catenin activation and suggest that HOMER3 might be a targetable vulnerability of TNBC.
BACKGROUND: HOMER family scaffolding proteins (HOMER1-3) play critical roles in the development and progression of human disease by regulating the assembly of signal transduction complexes in response to extrinsic stimuli. However, the role of HOMER protein in breast cancer remains unclear. METHODS:HOMER3 expression was examined by immunohistochemistry in breast cancerpatient specimens, and its significance in prognosis was assessed by Kaplan-Meier survival analysis. The effects of HOMER3 in growth factor-induced β-Catenin activation were analyzed by assays such as TOP/FOP flash reporter, tyrosine phosphorylation assay and reciprocal immunoprecipitation (IP) assay. Role of HOMER3 in breast cancer metastasis was determined by cell function assays and micetumor models. RESULTS: Herein, we find that, among the three HOMER proteins, HOMER3 is selectively overexpressed in the most aggressive triple negative breast cancer (TNBC) subtype, and significantly correlates with earlier tumor metastasis and shorter patient survival. Mechanismly, HOMER3 interacts with both c-Src and β-Catenin, thus providing a scaffolding platform to facilitate c-Src-induced β-Catenin tyrosine phosphorylation under growth factor stimulation. HOMER3 promotes β-Catenin nuclear translocation and activation, and this axis is clinically relevant. HOMER3 promotes and is essential for EGF-induced aggressiveness and metastasis of TNBC cells both in vitro and in vivo. CONCLUSION: These findings identify a novel role of HOMER3 in the transduction of growth factor-mediated β-Catenin activation and suggest that HOMER3 might be a targetable vulnerability of TNBC.
Authors: Ittai Ben-Porath; Matthew W Thomson; Vincent J Carey; Ruping Ge; George W Bell; Aviv Regev; Robert A Weinberg Journal: Nat Genet Date: 2008-05 Impact factor: 38.330
Authors: Kubra Karagoz; Heather L Lehman; Douglas B Stairs; Raghu Sinha; Kazim Y Arga Journal: Curr Cancer Drug Targets Date: 2016-02-02 Impact factor: 3.428