ISL1 promotes cancer progression and inhibits cisplatin sensitivity in triple-negative breast cancer cells

Zhang,Yang; Wang,Lu; Gao,Peng; Sun,Zhiguo; Li,Ning; Lu,Yanqin; Shen,Jianglun; Sun,Jian; Yang,Yiming; Dai,Hao; Cai,Haifeng

doi:10.3892/ijmm.2018.3842

ISL1 promotes cancer progression and inhibits cisplatin sensitivity in triple-negative breast cancer cells

Authors:
- Yang Zhang
- Lu Wang
- Peng Gao
- Zhiguo Sun
- Ning Li
- Yanqin Lu
- Jianglun Shen
- Jian Sun
- Yiming Yang
- Hao Dai
- Haifeng Cai
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Affiliations: The Second Department of Breast Surgery, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China, The Second Department of Chemoradiotherapy, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
Published online on: August 27, 2018 https://doi.org/10.3892/ijmm.2018.3842
Pages: 2343-2352
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triple‑negative breast cancer (TNBC) is a type of breast cancer that is characterized by the lack of expression of estrogen and progesterone receptors, and epidermal growth factor receptor 2. Therefore, there is an absence of a specific target for effective therapy in TNBC. Cisplatin is usually employed as a first‑line chemotherapy agent for patients with TNBC. However, resistance remains an obstacle for cisplatin‑based chemotherapy, due to its elusive underlying mechanism. Previously, abnormal expression of Islet 1 (ISL1) was demonstrated to be closely associated with cancer development and progression. The present study revealed that (ISL1) was significantly upregulated in TNBC tissues in comparison with adjacent normal tissues. Overexpression of ISL1 markedly promoted the proliferation and invasion of the TNBC MDA‑MB‑231 and MDA‑MB‑468 cell lines, while knockdown of ISL1 inhibited cell invasion and proliferation in these cell lines. In addition, overexpression of ISL1 reversed cisplatin‑induced cell apoptosis, while knockdown of ISL1 enhanced apoptosis following cisplatin treatment in MDA‑MB‑231 and MDA‑MB‑468 cells. Furthermore, the levels of the anti‑apoptotic proteins, phosphorylated‑protein kinase B and B‑cell lymphoma‑2 (Bcl‑2), were significantly decreased, while the levels of the pro‑apoptotic protein Bcl‑2‑associated X protein were remarkably increased in response to cisplatin treatment. The present study revealed that ISL1 overexpression reversed the protein expression profile of p‑Akt, Bcl‑2 and Bax, while ISL1 knockdown promoted cell apoptosis. Therefore, the data of the present study demonstrated that ISL1 contributes to TNBC progression and reverses cell sensitivity towards cisplatin in TNBC cells, suggesting that ISL1 is a potential therapeutic target for the treatment of TNBC.

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1	Patnaik JL, Byers T, DiGuiseppi C, Dabelea D and Denberg TD: Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: A retrospective cohort study. Breast Cancer Res. 13:R642011. View Article : Google Scholar : PubMed/NCBI
2	Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature. 490:61–70. 2012. View Article : Google Scholar : PubMed/NCBI
3	Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM and Nielsen TO: Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 14:1368–1376. 2008. View Article : Google Scholar : PubMed/NCBI
4	Oualla K, El-Zawahry HM, Arun B, Reuben JM, Woodward WA, Gamal El-Din H, Lim B, Mellas N, Ueno NT and Fouad TM: Novel therapeutic strategies in the treatment of triple-negative breast cancer. Ther Adv Med Oncol. 9:493–511. 2017. View Article : Google Scholar : PubMed/NCBI
5	Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, Quist J, Francesch-Domenech E, Plumb DA, Zakka L, Gazinska P, Liccardi G, et al: PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nat Med. 22:1303–1313. 2016. View Article : Google Scholar : PubMed/NCBI
6	Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y and Pietenpol JA: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 121:2750–2767. 2011. View Article : Google Scholar : PubMed/NCBI
7	Rakha EA, Reis-Filho JS and Ellis IO: Basal-like breast cancer: A critical review. J Clin Oncol. 26:2568–2581. 2008. View Article : Google Scholar : PubMed/NCBI
8	Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, Wang BY, Teng YE, Tong ZS, Pan YY, et al: Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): A randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 16:436–446. 2015. View Article : Google Scholar : PubMed/NCBI
9	Pruefer FG, Lizarraga F, Maldonado V and Melendez-Zajgla J: Participation of Omi Htra2 serine-protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells. J Chemother. 20:348–354. 2008. View Article : Google Scholar : PubMed/NCBI
10	Rottenberg S, Nygren AO, Pajic M, van Leeuwen FW, van der Heijden I, van de Wetering K, Liu X, de Visser KE, Gilhuijs KG, van Tellingen O, et al: Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci USA. 104:12117–12122. 2007. View Article : Google Scholar : PubMed/NCBI
11	Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M and Kroemer G: Molecular mechanisms of cisplatin resistance. Oncogene. 31:1869–1883. 2012. View Article : Google Scholar
12	Brozovic A and Osmak M: Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett. 251:1–16. 2007. View Article : Google Scholar
13	Zhou BP, Liao Y, Xia W, Spohn B, Lee MH and Hung MC: Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol. 3:245–252. 2001. View Article : Google Scholar : PubMed/NCBI
14	Karlsson O, Thor S, Norberg T, Ohlsson H and Edlund T: Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain. Nature. 344:879–882. 1990. View Article : Google Scholar : PubMed/NCBI
15	Hobert O and Westphal H: Functions of LIM-homeobox genes. Trends Genet. 16:75–83. 2000. View Article : Google Scholar : PubMed/NCBI
16	Guo C, Wang W, Shi Q, Chen P and Zhou C: An abnormally high expression of ISL-1 represents a potential prognostic factor in gastric cancer. Hum Pathol. 46:1282–1289. 2015. View Article : Google Scholar : PubMed/NCBI
17	Shin E, Lee Y and Koo JS: Differential expression of the epigenetic methylation-related protein DNMT1 by breast cancer molecular subtype and stromal histology. J Transl Med. 14:872016. View Article : Google Scholar : PubMed/NCBI
18	Livak and Schmittgen: 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
19	Elston CW and Ellis IO: Pathological prognostic factors in breast cancer. The value of histologic grade in breast cancer: Experience from a large study with long term follow-up. Histopathology. 19:403–410. 1991. View Article : Google Scholar : PubMed/NCBI
20	Kong X, Liu W and Kong Y: Roles and expression profiles of long non-coding RNAs in triple-negative breast cancers. J Cell Mol Med. 22:390–394. 2018. View Article : Google Scholar
21	Hansel DE, Rahman A, Hidalgo M, Thuluvath PJ, Lillemoe KD, Schulick R, Ku JL, Park JG, Miyazaki K, Ashfaq R, et al: Identification of novel cellular targets in biliary tract cancers using global gene expression technology. Am J Pathol. 163:217–229. 2003. View Article : Google Scholar : PubMed/NCBI
22	Schmitt AM, Riniker F, Anlauf M, Schmid S, Soltermann A, Moch H, Heitz PU, Klöppel G, Komminoth P and Perren A: Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases. Am J Surg Pathol. 32:420–425. 2008. View Article : Google Scholar : PubMed/NCBI
23	Erlenbach-Wünsch K, Haller F, Taubert H, Wurl P, Hartmann A and Agaimy A: Expression of the LIM homeobox domain transcription factor ISL1 (Islet-1) is frequent in rhabdomyosarcoma but very limited in other soft tissue sarcoma types. Pathology. 46:289–295. 2014. View Article : Google Scholar : PubMed/NCBI
24	Shi Q, Wang W, Jia Z, Chen P, Ma K and Zhou C: ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes, promotes gastric cancer cell proliferation and tumor growth. Oncotarget. 7:36489–36500. 2016. View Article : Google Scholar : PubMed/NCBI
25	Schlotter CM, Tietze L, Vogt U, Heinsen CV and Hahn A: Ki67 and lymphocytes in the pretherapeutic core biopsy of primary invasive breast cancer: Positive markers of therapy response prediction and superior survival. Horm Mol Biol Clin Investig. Sep 22–2017, (Epub ahead of print). doi: https://doi.org/10.1515/hmbci-2017-0022. View Article : Google Scholar
26	Wein L and Loi S: Mechanisms of resistance of chemotherapy in early-stage triple negative breast cancer (TNBC). Breast. 34(Suppl 1): S27–S30. 2017. View Article : Google Scholar : PubMed/NCBI
27	Gómez-Miragaya J, Palafox M, Paré L, Yoldi G, Ferrer I, Vila S, Galván P, Pellegrini P, Pérez-Montoyo H, Igea A, et al: Resistance to taxanes in triple-negative breast cancer associates with the dynamics of a CD49f+ tumor-initiating population. Stem Cell Reports. 8:1392–1407. 2017. View Article : Google Scholar : PubMed/NCBI
28	Saxena A, Viswanathan S, Moshynska O, Tandon P, Sankaran K and Sheridan DP: Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in B-cell chronic lymphocytic leukemia. Am J Hematol. 75:22–33. 2004. View Article : Google Scholar
29	Chen L, Cui H, Fang J, Deng H, Kuang P, Guo H, Wang X and Zhao L: Glutamine deprivation plus BPTES alters etoposide- and cisplatin-induced apoptosis in triple negative breast cancer cells. Oncotarget. 7:54691–54701. 2016.PubMed/NCBI
30	Liu S, Ren B, Gao H, Liao S, Zhai YX, Li S, Su XJ, Jin P, Stroncek D, Xu Z, et al: Over-expression of BAG-1 in head and neck squamous cell carcinomas (HNSCC) is associated with cisplatin-resistance. J Transl Med. 15:1892017. View Article : Google Scholar : PubMed/NCBI
31	Wen Q, Liu Y, Lyu H, Xu X, Wu Q, Liu N, Yin Q, Li J and Sheng X: Long noncoding RNA GAS5, which acts as a tumor suppressor via microRNA 21, regulates cisplatin resistance expression in cervical cancer. Int J Gynecol Cancer. 27:1096–1108. 2017. View Article : Google Scholar : PubMed/NCBI