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HOMER3 Facilitates Growth Factor-Mediated Β-Catenin Tyrosine

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HOMER3 Facilitates Growth Factor-Mediated Β-Catenin Tyrosine Liu et al. J Hematol Oncol (2021) 14:6 https://doi.org/10.1186/s13045-020-01021-x RESEARCH Open Access HOMER3 facilitates growth factor-mediated β-Catenin tyrosine phosphorylation and activation to promote metastasis in triple negative breast cancer 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 and Chuyong Lin1* Abstract Background: HOMER family scafolding 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. How- ever, the role of HOMER protein in breast cancer remains unclear. Methods: HOMER3 expression was examined by immunohistochemistry in breast cancer patient specimens, and its signifcance in prognosis was assessed by Kaplan–Meier survival analysis. The efects of HOMER3 in growth factor- induced β-Catenin activation were analyzed by assays such as TOP/FOP fash 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 fnd that, among the three HOMER proteins, HOMER3 is selectively overexpressed in the most aggressive triple negative breast cancer (TNBC) subtype, and signifcantly correlates with earlier tumor metastasis and shorter patient survival. Mechanismly, HOMER3 interacts with both c-Src and β-Catenin, thus providing a scafolding 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 fndings 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. Keywords: HOMER3, β-catenin, Tyrosine phosphorylation, Metastasis, TNBC Introduction Breast cancer incidence has increased steadily dur- ing the past decades and is currently the most common *Correspondence: [email protected] †Qinghua Liu, Lixin He and Siqi Li have contributed equally to this work malignancies in females worldwide [1]. Tere are four 1 State Key Laboratory of Oncology in Southern China and Department major subtypes of breast cancer: Luminal A, Luminal B, of Experimental Research, Collaborative Innovation Center for Cancer HER2 and Triple-negative breast cancer (TNBC). TNBC, Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China defned by lack of clinicopathological expression of hor- Full list of author information is available at the end of the article monal receptors and Her2, is the most aggressive subtype © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. J Hematol Oncol (2021) 14:6 Page 2 of 16 that accounts for only 15% of incidence but approximate evidence suggest that HOMER proteins may play impor- 30% of breast cancer-related deaths [2, 3]. TNBC could tant roles in carcinogenesis by afecting oncogenic path- not be treated with endocrine or targeted therapy [4]. ways. However, the roles of HOMER family in human Despite recent advances in chemotherapy, TNBC treat- breast cancer, especially in TNBC, are still unclear. ments are either transient or efective in a limited set of In the present study, we fnd that, among the HOMER patients, and can be associated with severe toxicity [5]. family members, HOMER3 is selectively overexpressed Moreover, TNBC cells are characterized by exceeding in TNBC and correlates with poor prognosis. Notably, mitotic, invasive, migratory features for distant dissemi- HOMER3 plays a scafolding function to simultane- nation, leading to frequent tumor recurrence [6]. Tus, ously interact with c-Src and β-Catenin and promotes the feld is in need of new biomarkers and therapeutic their efcient interactions, thus facilitating the growth targets. factor-induced β-Catenin tyrosine phosphorylation β-Catenin, central efector of Wnt signaling pathway, and activation. HOMER3 is essential for EGF-mediated mainly serves as a transcriptional co-activator of T-cell aggressiveness and metastasis both in vitro and in vivo. factors/lymphoid enhancer factor (TCFs/LEF) to dic- Tese fndings uncover the role of HOMER3 in growth- tate downstream genes transcription, and plays crucial factor-induced β-Catenin activation and TNBC metasta- roles in development and progression of human dis- sis, and open new avenues to prevent or overcome TNBC eases [7]. Unsurprisingly, β-Catenin activity is enriched by targeting HOMER3. in BLBC and predicts poor prognosis of TNBC patients [8, 9]. Studies have demonstrated aberrant activation of Materials and methods β-Catenin promotes cell migration, invasion and stem Cells cell-like properties of TNBC which encourage metastasis Breast cancer cell lines were obtained from the ATCC [10]. However, mutations of key components of Wnt/β- cultured following the provider’s recommendations. Catenin signaling pathway such as APC and β-Catenin MCF-7, T47D, MDA-MB-231 were grown in DMEM that have been proved to contribute to colorectal cancer, medium supplemented with 10% fetal bovine serum and other malignancies are not involved in the enrich- (FBS). ZR-75–1, BT-549 and 4T1 cells were maintained ment of β-Catenin signal in TNBC [11]. in RPMI-1640 medium with 10% FBS. SUM159PT cells Crosstalk between growth-factor signal transduction were maintained in Ham’s F-12 with 10% FBS. All cells and canonical Wnt pathway allows β-Catenin activation were supplemented with penicillin/streptomycin, hydro- in Wnt-independent ways. As a common joint of multi- cortisone, insulin, HEPES and L-glutamine, and main- ple signaling pathways, β-Catenin can be phosphorylated tained at 37 °C in 5% CO2. Cell lines were authenticated on tyrosine residues upon the efective stimulation of by short tandem repeat (STR) fngerprinting. growth factors, resulting in excessive β-Catenin nuclear translocation and transcriptional activation of targeted Patient information and tissue specimens genes in the context of malignant disease [12–14]. Nev- Tis study was conducted on a total of 347 paraf- ertheless, whether the aggressive traits of TNBC cells fn-embedded breast cancer samples including 256 could be attributed to the tyrosine phosphorylation of non-TNBCs and 91 TNBCs, which had been histopatho- β-Catenin remain largely elusive. logically and clinically diagnosed at the Sun Yat-sen HOMER family scafolding proteins comprise three University Cancer Center from 2005 to 2013. Clinico- members (HOMER1-3) in mammals [15, 16]. Whereas pathological characteristics are summarized in Addi- the carboxyl-terminal Coiled-coil self-assembly domain tional fle 7: Table 1. Ethics approval and prior patient allows HOMER proteins to build multimeric platform consent had been obtained from the Institutional for scafolding function, the enabled/vasodilator-stim- Research Ethics Committee for the use of the clinical ulated phosphoprotein homology 1 (EVH1) domain specimens for research purposes. located in amino-terminus is responsible for the recog- nition of diferent functional molecules such as phos- Immunohistochemistry (IHC) phoinositide 3-kinase enhancer long isoform (PIKE-L), IHC staining was performed on the 347 parafn-embed- group 1 metabotropic glutamate receptors (mGluRs), IP3 ded breast cancer tissue sections using HOMER3 and receptors (IP3R) and Shanks to participate in intracel- β-Catenin antibodies as previously reported [26]. Te lular calcium release and glutamatergic signaling trans- results of the staining were evaluated and scored by two duction [16–21]. Tese HOMER proteins predominately independent pathologists, who were blinded to the clini- expressed in the nervous system, peripheral tissues, and cal outcome. Te HOMER3 staining was graded with particularly in human cancers to regulate cell growth, four scores, strong + 3, moderate + 2, weak + 1, and nega- migration and apoptosis [20, 22–25]. Tese pieces of tive 0. Specimens with scores + 3, + 2 were defned as Liu et al. J Hematol Oncol (2021) 14:6 Page 3 of 16 high expression; while the others scored as + 1 or 0 were from those used in IP to avoid high background. For the low expression. On the other hand, specimens with >
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