GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis

Yin,Heng; Zhu,Qing; Liu,Manran; Tu,Gang; Li,Qing; Yuan,Jie; Wen,Siyang; Yang,Guanglun

doi:10.3892/ijo.2017.4117

GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis

Authors:
- Heng Yin
- Qing Zhu
- Manran Liu
- Gang Tu
- Qing Li
- Jie Yuan
- Siyang Wen
- Guanglun Yang
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Affiliations: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China, Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: September 5, 2017 https://doi.org/10.3892/ijo.2017.4117
Pages: 1191-1198

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Abstract

Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Our previous studies find that GPER and its down-stream signaling play a pivotal role in the development of tamoxifen (TAM) resistance. cDNA array analysis indicated a set of genes associated with cell apoptosis are aberrant in GPER activated and TAM-resistant MCF-7R cells compared with TAM-sensitive MCF-7 cells. Among these genes, Bim (also named BCL2-L11), a member of the BH3-only pro-apoptotic protein family is significantly decreased, and TRIM RING ﬁnger protein TRIM2 (a ubiquitin ligase) is highly expressed in MCF-7R. To understand the mechanism of TAM-resistance in GPER activated ER+ breast cancer, the function of TRIM2 and Bim inducing cell apoptosis was studied. By using immunohistochemical and western blot analysis, there is an adverse correlation between TRIM2 and Bim in TAM-resistant breast tumor tissues and MCF-7R cells. Knockdown Bim in TAM-sensitive MCF-7 cells or overexpression of Bim in TAM-resistant MCF-7 cells significantly changed its sensibility to TAM through altering the levels of cleaved PARP and caspase-3. Activation of GPER and its downstream signaling MAPK/ERK, not PI3K/AKT, led to enhanced TRIM2 protein levels and affected the binding between TRIM2 and Bim which resulted in a reduced Bim in TAM-resistant breast cancer cells. Thus, the present study provides a novel insight to TAM-resistance in ER-positive breast cancer cells.

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1	Briest S and Stearns V: Tamoxifen metabolism and its effect on endocrine treatment of breast cancer. Clin Adv Hematol Oncol. 7:185–192. 2009.PubMed/NCBI
2	Yuan J, Liu M, Yang L, Tu G, Zhu Q, Chen M, Cheng H, Luo H, Fu W, Li Z, et al: Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: A new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells. Breast Cancer Res. 17:692015. View Article : Google Scholar
3	Willis SN and Adams JM: Life in the balance: How BH3-only proteins induce apoptosis. Curr Opin Cell Biol. 17:617–625. 2005. View Article : Google Scholar : PubMed/NCBI
4	Strasser A: The role of BH3-only proteins in the immune system. Nat Rev Immunol. 5:189–200. 2005. View Article : Google Scholar : PubMed/NCBI
5	Villunger A, Scott C, Bouillet P and Strasser A: Essential role for the BH3-only protein Bim but redundant roles for Bax, Bcl-2, and Bcl-w in the control of granulocyte survival. Blood. 101:2393–2400. 2003. View Article : Google Scholar
6	Kirschnek S, Vier J, Gautam S, Frankenberg T, Rangelova S, Eitz-Ferrer P, Grespi F, Ottina E, Villunger A, Häcker H, et al: Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa. Cell Death Differ. 18:1805–1814. 2011. View Article : Google Scholar : PubMed/NCBI
7	Huang WF, Liu AH, Zhao HJ, Dong HM, Liu LY and Cai SX: BIM gene polymorphism lowers the efficacy of EGFR-TKIs in advanced nonsmall cell lung cancer with sensitive EGFR mutations: A systematic review and meta-analysis. Medicine (Baltimore). 94:e12632015.J. View Article : Google Scholar
8	Gu Z, Wang X, Qi R, Wei L, Huo Y, Ma Y, Shi L, Chang Y, Li G and Zhou L: Oridonin induces apoptosis in uveal melanoma cells by upregulation of Bim and downregulation of Fatty Acid Synthase. Biochem Biophys Res Commun. 457:187–193. 2015. View Article : Google Scholar
9	Merino D, Best SA, Asselin-Labat ML, Vaillant F, Pal B, Dickins RA, Anderson RL, Strasser A, Bouillet P, Lindeman GJ, et al: Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2. Oncogene. 34:3926–3934. 2015. View Article : Google Scholar
10	Park SH, Ito K, Olcott W, Katsyv I, Halstead-Nussloch G and Irie HY: PTK6 inhibition promotes apoptosis of Lapatinib-resistant Her2⁺ breast cancer cells by inducing Bim. Breast Cancer Res. 17:862015. View Article : Google Scholar
11	Follin-Arbelet V, Misund K, Naderi EH, Ugland H, Sundan A and Blomhoff HK: The natural compound forskolin synergizes with dexamethasone to induce cell death in myeloma cells via BIM. Sci Rep. 5:130012015. View Article : Google Scholar : PubMed/NCBI
12	Reginato MJ, Mills KR, Becker EB, Lynch DK, Bonni A, Muthuswamy SK and Brugge JS: Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes. Mol Cell Biol. 25:4591–4601. 2005. View Article : Google Scholar : PubMed/NCBI
13	Dai Y and Grant S: BCL2L11/Bim as a dual-agent regulating autophagy and apoptosis in drug resistance. Autophagy. 11:416–418. 2015. View Article : Google Scholar : PubMed/NCBI
14	Hatakeyama S: TRIM proteins and cancer. Nat Rev Cancer. 11:792–804. 2011. View Article : Google Scholar : PubMed/NCBI
15	Zoumpoulidou G, Broceño C, Li H, Bird D, Thomas G and Mittnacht S: Role of the tripartite motif protein 27 in cancer development. J Natl Cancer Inst. 104:941–952. 2012. View Article : Google Scholar : PubMed/NCBI
16	Liu C, Huang X, Hou S, Hu B and Li H: Silencing of tripartite motif (TRIM) 29 inhibits proliferation and invasion and increases chemosensitivity to cisplatin in human lung squamous cancer NCI-H520 cells. Thorac Cancer. 6:31–37. 2015. View Article : Google Scholar : PubMed/NCBI
17	Ozato K, Shin DM, Chang TH and Morse HC III: TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol. 8:849–860. 2008. View Article : Google Scholar : PubMed/NCBI
18	Qiu F, Xiong JP, Deng J and Xiang XJ: TRIM29 functions as an oncogene in gastric cancer and is regulated by miR-185. Int J Clin Exp Pathol. 8:5053–5061. 2015.PubMed/NCBI
19	Wang Y and He D, Yang L, Wen B, Dai J, Zhang Q, Kang J, He W, Ding Q and He D: TRIM26 functions as a novel tumor suppressor of hepatocellular carcinoma and its downregulation contributes to worse prognosis. Biochem Biophys Res Commun. 463:458–465. 2015. View Article : Google Scholar : PubMed/NCBI
20	Williams MD, Zhang L, Elliott DD, Perrier ND, Lozano G, Clayman GL and El-Naggar AK: Differential gene expression profiling of aggressive and nonaggressive follicular carcinomas. Hum Pathol. 42:1213–1220. 2011. View Article : Google Scholar : PubMed/NCBI
21	Ivanov SV, Panaccione A, Nonaka D, Prasad ML, Boyd KL, Brown B, Guo Y, Sewell A and Yarbrough WG: Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas. Br J Cancer. 109:444–451. 2013. View Article : Google Scholar : PubMed/NCBI
22	Thompson S, Pearson AN, Ashley MD, Jessick V, Murphy BM, Gafken P, Henshall DC, Morris KT, Simon RP and Meller R: Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. J Biol Chem. 286:19331–19339. 2011. View Article : Google Scholar : PubMed/NCBI
23	Balastik M, Ferraguti F, Pires-da Silva A, Lee TH, Alvarez-Bolado G, Lu KP and Gruss P: Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc Natl Acad Sci USA. 105:12016–12021. 2008. View Article : Google Scholar : PubMed/NCBI
24	Mo Z, Liu M, Yang F, Luo H, Li Z, Tu G and Yang G: GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer. Breast Cancer Res. 15:R1142013. View Article : Google Scholar : PubMed/NCBI
25	Ignatov A, Ignatov T, Weissenborn C, Eggemann H, Bischoff J, Semczuk A, Roessner A, Costa SD and Kalinski T: G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. Breast Cancer Res Treat. 128:457–466. 2011. View Article : Google Scholar : PubMed/NCBI
26	Ignatov A, Ignatov T, Roessner A, Costa SD and Kalinski T: Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells. Breast Cancer Res Treat. 123:87–96. 2010. View Article : Google Scholar
27	Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA and Hathaway HJ: Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu Rev Physiol. 70:165–190. 2008. View Article : Google Scholar : PubMed/NCBI
28	Fujiwara S, Terai Y, Kawaguchi H, Takai M, Yoo S, Tanaka Y, Tanaka T, Tsunetoh S, Sasaki H, Kanemura M, et al: GPR30 regulates the EGFR-Akt cascade and predicts lower survival in patients with ovarian cancer. J Ovarian Res. 5:352012. View Article : Google Scholar : PubMed/NCBI
29	Filardo EJ, Quinn JA, Bland KI and Frackelton AR Jr: Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol. 14:1649–1660. 2015. View Article : Google Scholar
30	Lv Y, Song S, Zhang K, Gao H and Ma R: CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells. PLoS One. 8:e833122013. View Article : Google Scholar :
31	Periyasamy-Thandavan S, Takhar S, Singer A, Dohn MR, Jackson WH, Welborn AE, LeRoith D, Marrero M, Thangaraju M, Huang S, et al: Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER⁺ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim. Breast Cancer Res. 14:R522012. View Article : Google Scholar
32	Yu T, Liu M, Luo H, Wu C, Tang X, Tang S, Hu P, Yan Y, Wang Z and Tu G: GPER mediates enhanced cell viability and motility via non-genomic signaling induced by 17β-estradiol in triple-negative breast cancer cells. J Steroid Biochem Mol Biol. 143:392–403. 2014. View Article : Google Scholar : PubMed/NCBI
33	Wu K, Li A, Rao M, Liu M, Dailey V, Yang Y, Di Vizio D, Wang C, Lisanti MP, Sauter G, et al: DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth. Mol Cell Biol. 26:7116–7129. 2006. View Article : Google Scholar : PubMed/NCBI
34	Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, Powell MJ, Yang T, Gu W, Avantaggiati ML, et al: Hormonal control of androgen receptor function through SIRT1. Mol Cell Biol. 26:8122–8135. 2006. View Article : Google Scholar : PubMed/NCBI
35	Han BJ, Li W, Jiang GB, Lai SH, Zhang C, Zeng CC and Liu YJ: Effects of daidzein in regards to cytotoxicity in vitro, apoptosis, reactive oxygen species level, cell cycle arrest and the expression of caspase and Bcl-2 family proteins. Oncol Rep. 34:1115–1120. 2015. View Article : Google Scholar : PubMed/NCBI
36	Tomicic MT, Meise R, Aasland D, Berte N, Kitzinger R, Krämer OH, Kaina B and Christmann M: Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. Oncotarget. 6:33755–33768. 2015. View Article : Google Scholar : PubMed/NCBI
37	Zhang LM, Zhao XC, Sun WB, Li R and Jiang XJ: Sevoflurane post-conditioning protects primary rat cortical neurons against oxygen-glucose deprivation/resuscitation via down-regulation in mitochondrial apoptosis axis of Bid, Bim, Puma-Bax and Bak mediated by Erk1/2. J Neurol Sci. 357:80–87. 2015. View Article : Google Scholar : PubMed/NCBI
38	Hiscox S, Jiang WG, Obermeier K, Taylor K, Morgan L, Burmi R, Barrow D and Nicholson RI: Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of β-catenin phosphorylation. Int J Cancer. 118:290–301. 2006. View Article : Google Scholar
39	Ward A, Balwierz A, Zhang JD, Küblbeck M, Pawitan Y, Hielscher T, Wiemann S and Sahin Ö: Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene. 32:1173–1182. 2013. View Article : Google Scholar
40	Thewes V, Simon R, Schroeter P, Schlotter M, Anzeneder T, Büttner R, Benes V, Sauter G, Burwinkel B, Nicholson RI, et al: Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer. Cancer Res. 75:720–731. 2015. View Article : Google Scholar : PubMed/NCBI