SHOC2 is associated with the survival of breast cancer cells and has prognostic value for patients with breast cancer

Geng,Wenwen; Dong,Ke; Pu,Qian; Lv,Yanrong; Gao,Haidong

doi:10.3892/mmr.2019.10889

SHOC2 is associated with the survival of breast cancer cells and has prognostic value for patients with breast cancer

Authors:
- Wenwen Geng
- Ke Dong
- Qian Pu
- Yanrong Lv
- Haidong Gao
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Affiliations: Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China, Department of Breast Surgery, Qilu Hospital (Qingdao) of Shandong University, Qingdao, Shandong 266000, P.R. China
Published online on: December 17, 2019 https://doi.org/10.3892/mmr.2019.10889
Pages: 867-875
Copyright: © Geng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

SHOC2 leucine rich repeat scaffold protein (SHOC2) has been identified as a positive regulator of the Ras pathway; however, the function of SHOC2 in breast cancer has rarely been explored. The current study investigated the effects of SHOC2 on breast cancer cell growth and evaluated its prognostic value in patients with breast cancer. The effects of SHOC2 on MCF‑7 and MDA‑MB‑231 breast cancer cells were studied using short hairpin RNA. In total, 120 pairs of formalin‑fixed, paraffin‑embedded breast cancer tissue specimens were compared to normal tissue using immunohistochemical staining. SHOC2 knockdown significantly inhibited MCF‑7 and MDA‑MB‑231 breast cancer cell proliferation, and induced cell apoptosis and cell cycle arrest. Additionally, the RAS‑MAPK/PI3K pathway was inhibited by SHOC2 knockdown. In a clinical study, the results revealed that high SHOC2 expression was associated with more aggressive clinical characteristics of breast cancer. Moreover, Kaplan‑Meier and Cox regression analyses indicated that SHOC2 expression was an independent prognostic factor for survival, suggesting that increased SHOC2 expression predicted a worse overall survival. This indicated that SHOC2 knockdown could affect breast cancer cell survival, and SHOC2 upregulation may be associated with a poor prognosis in patients with breast cancer.

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1	Ban KA and Godellas CV: Epidemiology of breast cancer. Surg Oncol Clin N Am. 23:409–422. 2014. View Article : Google Scholar : PubMed/NCBI
2	Lee EY and Muller WJ: Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol. 2:a0032362010. View Article : Google Scholar : PubMed/NCBI
3	Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 3:11–22. 2003. View Article : Google Scholar : PubMed/NCBI
4	Sieburth DS, Sun Q and Han M: SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans. Cell. 94:119–130. 1998. View Article : Google Scholar : PubMed/NCBI
5	Jang ER, Jang H, Shi P, Popa G, Jeoung M and Galperin E: Spatial control of Shoc2-scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5. J Cell Sci. 128:4428–4441. 2015. View Article : Google Scholar : PubMed/NCBI
6	Matsunaga-Udagawa R, Fujita Y, Yoshiki S, Terai K, Kamioka Y, Kiyokawa E, Yugi K, Aoki K and Matsuda M: The scaffold protein Shoc2/SUR-8 accelerates the interaction of Ras and Raf. J Biol Chem. 285:7818–7826. 2010. View Article : Google Scholar : PubMed/NCBI
7	Li W, Han M and Guan KL: The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Genes Dev. 14:895–900. 2000.PubMed/NCBI
8	Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M and McCormick F: A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Mol Cell. 22:217–230. 2006. View Article : Google Scholar : PubMed/NCBI
9	Shaw AS and Filbert EL: Scaffold proteins and immune-cell signalling. Nat Rev Immunol. 9:47–56. 2009. View Article : Google Scholar : PubMed/NCBI
10	Rouchka EC, Jeoung M, Jang ER, Liu J, Wang C, Li X and Galperin E: Data set for transcriptional response to depletion of the Shoc2 scaffolding protein. Data Brief. 7:770–778. 2016. View Article : Google Scholar : PubMed/NCBI
11	Young LC, Hartig N, Munoz-Alegre M, Oses-Prieto JA, Durdu S, Bender S, Vijayakumar V, Vietri Rudan M, Gewinner C, Henderson S, et al: An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth. Mol Cell. 52:679–692. 2013. View Article : Google Scholar : PubMed/NCBI
12	Lee YM, Kaduwal S, Lee KH, Park JC, Jeong WJ and Choi KY: Sur8 mediates tumorigenesis and metastasis in colorectal cancer. Exp Mol Med. 48:e2492016. View Article : Google Scholar : PubMed/NCBI
13	Kaduwal S, Jeong WJ, Park JC, Lee KH, Lee YM, Jeon SH, Lim YB, Min do S and Choi KY: Sur8/Shoc2 promotes cell motility and metastasis through activation of Ras-PI3K signaling. Oncotarget. 6:33091–33105. 2015. View Article : Google Scholar : PubMed/NCBI
14	Kaplan FM, Kugel CH III, Dadpey N, Shao Y, Abel EV and Aplin AE: SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor. J Biol Chem. 287:41797–41807. 2012. View Article : Google Scholar : PubMed/NCBI
15	Traini S, Piccolo E, Tinari N, Rossi C, La Sorda R, Spinella F, Bagnato A, Lattanzio R, D'Egidio M, Di Risio A, et al: Inhibition of tumor growth and angiogenesis by SP-2, an anti-lectin, galactoside-binding soluble 3 binding protein (LGALS3BP) antibody. Mol Cancer Ther. 13:916–925. 2014. View Article : Google Scholar : PubMed/NCBI
16	Jeoung M, Jang ER, Liu J, Wang C, Rouchka EC, Li X and Galperin E: Shoc2-tranduced ERK1/2 motility signals--Novel insights from functional genomics. Cell Signal. 28:448–459. 2016. View Article : Google Scholar : PubMed/NCBI
17	Aran D, Camarda R, Odegaard J, Paik H, Oskotsky B, Krings G, Goga A, Sirota M and Butte AJ: Comprehensive analysis of normal adjacent to tumor transcriptomes. Nat Commun. 8:10772017. View Article : Google Scholar : PubMed/NCBI
18	Li C, Cao L, Xu C, Liu F, Xiang G, Liu X, Jiao J and Niu Y: The immunohistochemical expression and potential prognostic value of HDAC6 and AR in invasive breast cancer. Hum Pathol. 75:16–25. 2018. View Article : Google Scholar : PubMed/NCBI
19	Ye W, Chen C, Gao Y, Zheng ZS, Xu Y, Yun M, Weng HW, Xie D, Ye S and Zhang JX: Overexpression of SLC34A2 is an independent prognostic indicator in bladder cancer and its depletion suppresses tumor growth via decreasing c-Myc expression and transcriptional activity. Cell Death Dis. 8:e25812017. View Article : Google Scholar : PubMed/NCBI
20	Shen Q, Yao Q, Sun J, Feng L, Lu H, Ma Y, Liu L, Wang F, Li J, Yue Y, et al: Downregulation of histone deacetylase 1 by microRNA-520h contributes to the chemotherapeutic effect of doxorubicin. FEBS Lett. 588:184–191. 2014. View Article : Google Scholar : PubMed/NCBI
21	Lin X, Yu Y, Zhao H, Zhang Y, Manela J and Tonetti DA: Overexpression of PKCalpha is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model. Carcinogenesis. 27:1538–1546. 2006. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Clark GJ and Der CJ: Aberrant function of the Ras signal transduction pathway in human breast cancer. Breast Cancer Res Treat. 35:133–144. 1995. View Article : Google Scholar : PubMed/NCBI
24	Eckert LB, Repasky GA, Ulku AS, McFall A, Zhou H, Sartor CI and Der CJ: Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res. 64:4585–4592. 2004. View Article : Google Scholar : PubMed/NCBI
25	Jones GG, Del Rio IB, Sari S, Sekerim A, Young LC, Hartig N, Areso Zubiaur I, El-Bahrawy MA, Hynds RE, Lei W, et al: SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers. Nat Commun. 10:25322019. View Article : Google Scholar : PubMed/NCBI
26	Jang ER and Galperin E: The function of Shoc2: A scaffold and beyond. Commun Integr Biol. 9:e11882412016. View Article : Google Scholar : PubMed/NCBI
27	Loboda A, Nebozhyn M, Klinghoffer R, Frazier J, Chastain M, Arthur W, Roberts B, Zhang T, Chenard M, Haines B, et al: A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med Genomics. 3:262010. View Article : Google Scholar : PubMed/NCBI
28	Li W, Liang RR, Zhou C, Wu MY, Lian L, Yuan GF, Wang MY, Xie X, Shou LM, Gong FR, et al: The association between expressions of Ras and CD68 in the angiogenesis of breast cancers. Cancer Cell Int. 15:172015. View Article : Google Scholar : PubMed/NCBI