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Pathology & Oncology Research

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07.06.2019 | Original Article

CUL1 Knockdown Attenuates the Adhesion, Invasion, and Migration of Triple-Negative Breast Cancer Cells via Inhibition of Epithelial-Mesenchymal Transition

verfasst von: Ze-Qiang Ren, Wen-Jing Yan, Xiu-Zhong Zhang, Peng-Bo Zhang, Chong Zhang, Shou-Kun Chen

Erschienen in: Pathology & Oncology Research | Ausgabe 2/2020

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Abstract

Cullin-1 (CUL1) is an important factor for tumor growth and a potential therapeutic target for breast cancer therapy, but the molecular mechanism in triple-negative breast cancer (TNBC) is unknown. In the present study, CUL1 shRNA was transfected into BT549 and MDA-MB-231 breast cancer cells. Cell morphology, adhesion, invasion, and migration assays were carried out in the CUL1 knockdown cells. Additionally, protein expression levels of epithelial-mesenchymal transition (EMT)-related factors, Akt phosphorylation at S473 (pAkt), glycogen synthase kinase-3β phosphorylation at ser9 (pGSK3β), cytoplasmic and nuclear β-catenin, and epidermal growth factor receptor phosphorylation at Tyr1068 (pEGFR) were detected by Western blot analysis. CUL1 knockdown significantly suppressed the adhesion, invasion and migration capabilities of the cells, and decreased the expression of Snail1/2, ZEB1/2, Twist1/2, Vimentin, and increased the expression of Cytokeratin 18 (CK18). Moreover, CUL1 knockdown significantly downregulated the phosphorylated levels of Akt, GSK3β, and EGFR, inhibiting the translocation of β-catenin from the cytoplasm to the nucleus. The results indicate that CUL1 knockdown prohibited the metastasis behaviors of breast cancer cells through downregulation (dephosphorylation) of the EMT signaling pathways of EGFR and Akt/GSK3β/β-catenin in breast cancer. These results strongly suggested that reinforcement of the EMT might be a key for CUL1 to accelerate TNBC metastasis.

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108. https://doi.org/10.3322/caac.21262 CrossRefPubMed

Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina breast Cancer study. JAMA 295(21):2492–2502. https://doi.org/10.1001/jama.295.21.2492 CrossRefPubMed

Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. https://doi.org/10.1038/35021093 CrossRefPubMed

Sarikas A, Hartmann T, Pan ZQ (2011) The cullin protein family. Genome Biol 12(4):220. https://doi.org/10.1186/gb-2011-12-4-220 CrossRefPubMedPubMedCentral

Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6(5):369–381. https://doi.org/10.1038/nrc1881 CrossRefPubMed

Chen GD, Li G (2010) Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression. Int J Oncol 37(5):1339–1344. https://doi.org/10.3892/Ijo_00000786 CrossRefPubMed

Zhang Q, Chen Q, Lu X, Zhou Z, Zhang H, Lin HY, Duan E, Zhu C, Tan Y, Wang H (2013) CUL1 promotes trophoblast cell invasion at the maternal-fetal interface. Cell Death Dis 4. ARTN e502. https://doi.org/10.1038/cddis.2013.1 CrossRef

Xu M, Yang X, Zhao J, Zhang J, Zhang S, Huang H, Liu Y, Liu J (2014) High expression of Cullin1 indicates poor prognosis for NSCLC patients. Pathol Res Pract 210(7):397–401. https://doi.org/10.1016/j.prp.2014.01.015 CrossRefPubMed

Bai J, Zhou Y, Chen GD, Zeng JY, Ding JJ, Tan YF, Zhou JW, Li G (2011) Overexpression of Cullin1 is associated with poor prognosis of patients with gastric cancer. Hum Pathol 42(3):375–383. https://doi.org/10.1016/j.humpath.2010.09.003 CrossRefPubMed

10.

Bai J, Yong HM, Chen FF, Mei PJ, Liu H, Li C, Pan ZQ, Wu YP, Zheng JN (2013) Cullin1 is a novel marker of poor prognosis and a potential therapeutic target in human breast cancer. Ann Oncol 24(8):2016–2022. https://doi.org/10.1093/annonc/mdt147 CrossRefPubMed

11.

Zhang J, Liu D, Feng Z, Mao J, Zhang C, Lu Y, Li J, Zhang Q, Li Q, Li L (2016) MicroRNA-138 modulates metastasis and EMT in breast cancer cells by targeting vimentin. Biomed Pharmacother 77:135–141. https://doi.org/10.1016/j.biopha.2015.12.018 CrossRefPubMed

12.

Jung H, Kim B, Moon BI, Oh ES (2016) Cytokeratin 18 is necessary for initiation of TGF-beta1-induced epithelial-mesenchymal transition in breast epithelial cells. Mol Cell Biochem 423(1–2):21–28. https://doi.org/10.1007/s11010-016-2818-7 CrossRefPubMed

13.

Avizienyte E, Frame MC (2005) Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition. Curr Opin Cell Biol 17(5):542–547. https://doi.org/10.1016/j.ceb.2005.08.007 CrossRefPubMed

14.

Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grunert S (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156(2):299–313. https://doi.org/10.1083/jcb.200109037 CrossRefPubMedPubMedCentral

15.

Yan D, Avtanski D, Saxena NK, Sharma D (2012) Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires beta-catenin activation via Akt/GSK3- and MTA1/Wnt1 protein-dependent pathways. J Biol Chem 287(11):8598–8612. https://doi.org/10.1074/jbc.M111.322800 CrossRefPubMedPubMedCentral

16.

Zhao J, Ou B, Han D, Wang P, Zong Y, Zhu C, Liu D, Zheng M, Sun J, Feng H, Lu A (2017) Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/snail and AKT/GSK3beta/beta-catenin pathways. Mol Cancer 16(1):70. https://doi.org/10.1186/s12943-017-0629-4 CrossRefPubMedPubMedCentral

17.

Kenny PA, Bissell MJ (2007) Targeting TACE-dependent EGFR ligand shedding in breast cancer. J Clin Invest 117(2):337–345. https://doi.org/10.1172/JCI29518 CrossRefPubMedPubMedCentral

18.

Buchholz TA, Tu X, Ang KK, Esteva FJ, Kuerer HM, Pusztai L, Cristofanilli M, Singletary SE, Hortobagyi GN, Sahin AA (2005) Epidermal growth factor receptor expression correlates with poor survival in patients who have breast carcinoma treated with doxorubicin-based neoadjuvant chemotherapy. Cancer 104(4):676–681. https://doi.org/10.1002/cncr.21217 CrossRefPubMed

19.

Davison Z, de Blacquiere GE, Westley BR, May FE (2011) Insulin-like growth factor-dependent proliferation and survival of triple-negative breast cancer cells: implications for therapy. Neoplasia 13(6):504–515CrossRefPubMedPubMedCentral

20.

Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry. Cancer 109(9):1721–1728. https://doi.org/10.1002/cncr.22618 CrossRefPubMed

21.

Li X, Ma Q, Xu Q, Liu H, Lei J, Duan W, Bhat K, Wang F, Wu E, Wang Z (2012) SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of hedgehog pathway. Cancer Lett 322(2):169–176. https://doi.org/10.1016/j.canlet.2012.02.035 CrossRefPubMedPubMedCentral

22.

Wu J, Liu W, Williams JP, Ratner N (2017) EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation. Oncogene 36(12):1669–1677. https://doi.org/10.1038/onc.2016.386 CrossRefPubMed

23.

Liu Y, Ji R, Li J, Gu Q, Zhao X, Sun T, Wang J, Li J, Du Q, Sun B (2010) Correlation effect of EGFR and CXCR4 and CCR7 chemokine receptors in predicting breast cancer metastasis and prognosis. J Exp Clin Cancer Res 29:16. https://doi.org/10.1186/1756-9966-29-16 CrossRefPubMedPubMedCentral

24.

Yamashita N, Tokunaga E, Kitao H, Hisamatsu Y, Taketani K, Akiyoshi S, Okada S, Aishima S, Morita M, Maehara Y (2013) Vimentin as a poor prognostic factor for triple-negative breast cancer. J Cancer Res Clin 139(5):739–746. https://doi.org/10.1007/s00432-013-1376-6 CrossRef

25.

Jeong H, Ryu YJ, An J, Lee Y, Kim A (2012) Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype. Histopathology 60(6B):E87–E95. https://doi.org/10.1111/j.1365-2559.2012.04195.x CrossRefPubMed

26.

Ghahhari NM, Babashah S (2015) Interplay between microRNAs and WNT/beta-catenin signalling pathway regulates epithelial-mesenchymal transition in cancer. Eur J Cancer 51(12):1638–1649. https://doi.org/10.1016/j.ejca.2015.04.021 CrossRefPubMed

27.

Weyemi U, Redon CE, Sethi TK, Burrell AS, Jailwala P, Kasoji M, Abrams N, Merchant A, Bonner WM (2016) Twist1 and slug mediate H2AX-regulated epithelial-mesenchymal transition in breast cells. Cell Cycle 15(18):2398–2404. https://doi.org/10.1080/15384101.2016.1198864 CrossRefPubMedPubMedCentral

28.

Pan Y, Zhang J, Fu H, Shen L (2016) miR-144 functions as a tumor suppressor in breast cancer through inhibiting ZEB1/2-mediated epithelial mesenchymal transition process. Onco Targets Ther 9:6247–6255. https://doi.org/10.2147/OTT.S103650 CrossRefPubMedPubMedCentral

29.

Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW, Waltham M (2007) Vimentin and epithelial-mesenchymal transition in human breast cancer--observations in vitro and in vivo. Cells Tissues Organs 185(1–3):191–203. https://doi.org/10.1159/000101320 CrossRefPubMed

30.

Kumar A, Pandurangan AK, Lu F, Fyrst H, Zhang M, Byun HS, Bittman R, Saba JD (2012) Chemopreventive sphingadienes downregulate Wnt signaling via a PP2A/Akt/GSK3beta pathway in colon cancer. Carcinogenesis 33(9):1726–1735. https://doi.org/10.1093/carcin/bgs174 CrossRefPubMedPubMedCentral

31.

Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z (2007) Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282(15):11221–11229. https://doi.org/10.1074/jbc.M611871200 CrossRefPubMed

32.

Wang C, Jin H, Wang N, Fan S, Wang Y, Zhang Y, Wei L, Tao X, Gu D, Zhao F, Fang J, Yao M, Qin W (2016) Gas6/Axl Axis contributes to Chemoresistance and metastasis in breast Cancer through Akt/GSK-3beta/beta-catenin signaling. Theranostics 6(8):1205–1219. https://doi.org/10.7150/thno.15083 CrossRefPubMedPubMedCentral

33.

Geyer FC, Lacroix-Triki M, Savage K, Arnedos M, Lambros MB, MacKay A, Natrajan R, Reis-Filho JS (2011) Beta-catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Modern Pathol 24(2):209–231. https://doi.org/10.1038/modpathol.2010.205 CrossRef

34.

Li J, Zhou BP (2011) Activation of beta-catenin and Akt pathways by twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11:49. https://doi.org/10.1186/1471-2407-11-49 CrossRefPubMedPubMedCentral

35.

Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu HJ, Walker F, Frenkel MJ, Hoyne PA, Jorissen RN, Nice EC, Burgess AW, Ward CW (2002) Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell 110(6):763–773CrossRefPubMed

36.

Corkery B, Crown J, Clynes M, O'Donovan N (2009) Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann Oncol 20(5):862–867. https://doi.org/10.1093/annonc/mdn710 CrossRefPubMed

37.

Xu W, Yang Z, Lu N (2015) A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes Migr 9(4):317–324. https://doi.org/10.1080/19336918.2015.1016686 CrossRef

38.

Patil PU, D'Ambrosio J, Inge LJ, Mason RW, Rajasekaran AK (2015) Carcinoma cells induce lumen filling and EMT in epithelial cells through soluble E-cadherin-mediated activation of EGFR. J Cell Sci 128(23):4366–4379. https://doi.org/10.1242/jcs.173518 CrossRefPubMedPubMedCentral

Titel: CUL1 Knockdown Attenuates the Adhesion, Invasion, and Migration of Triple-Negative Breast Cancer Cells via Inhibition of Epithelial-Mesenchymal Transition
verfasst von: Ze-Qiang Ren
Wen-Jing Yan
Xiu-Zhong Zhang
Peng-Bo Zhang
Chong Zhang
Shou-Kun Chen
Publikationsdatum: 07.06.2019
Verlag: Springer Netherlands
Erschienen in: Pathology & Oncology Research / Ausgabe 2/2020
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-019-00681-6

Springer Medizin

CUL1 Knockdown Attenuates the Adhesion, Invasion, and Migration of Triple-Negative Breast Cancer Cells via Inhibition of Epithelial-Mesenchymal Transition

Abstract

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Abstract

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