Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells

Kim,Sangmin; Lee,Jeongmin; Oh,Soo  Jin; Nam,Seok  Jin; Lee,Jeong  Eon

doi:10.3892/or.2015.4116

Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells

Authors:
- Sangmin Kim
- Jeongmin Lee
- Soo Jin Oh
- Seok Jin Nam
- Jeong Eon Lee
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Affiliations: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea
Published online on: July 8, 2015 https://doi.org/10.3892/or.2015.4116
Pages: 1613-1619

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Abstract

Although tamoxifen is the most common and effective therapy for treatment of estrogen receptor-α (ER-α) breast cancer patients, resistance of endocrine therapy occurs, either de novo or acquired during therapy. Here, we investigated the clinical value of epidermal growth factor receptor (EGFR) in tamoxifen-resistant (TamR) patients and the differential effect of EGFR inhibitors, neratinib and gefitinib, on TamR breast cancer cell model. The morphology of TamR MCF7 cells showed mesenchymal phenotypes and did not induce cell death by tamoxifen treatment compared with tamoxifen‑sensitive (TamS) MCF7 cells. In addition, mesenchymal marker proteins, including N-cadherin (N-cad), fibronectin (FN), and Slug, significantly increased in TamR cells. In contrast, ER-α and E-cadherin (E-cad) were greatly decreased. We also found that the levels of EGFR and HER2 expression were increased in TamR cells. Furthermore, we observed that EGFR expression was directly involved with poor prognosis of tamoxifen-treated breast cancer patients using the GSE1378 date set. Thus, we treated TamR and TamS cells with EGFR inhibitors, neratinib and gefitinib, respectively. Interestingly, neratinib induced apoptotic cell death of TamR but not gefitinib. Cleaved PARP-1 expression was also increased by neratinib treatment in TamR cells. Therefore, we suggest that neratinib may be a potential therapeutic drug for treating TamR breast cancer.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
2	Osborne CK, Zhao H and Fuqua SA: Selective estrogen receptor modulators: structure, function, and clinical use. J Clin Oncol. 18:3172–3186. 2000.PubMed/NCBI
3	Harvey JM, Clark GM, Osborne CK and Allred DC: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 17:1474–1481. 1999.PubMed/NCBI
4	Herynk MH and Fuqua SA: Estrogen receptors in resistance to hormone therapy. Adv Exp Med Biol. 608:130–143. 2007. View Article : Google Scholar : PubMed/NCBI
5	Ali S and Coombes RC: Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2:101–112. 2002. View Article : Google Scholar
6	Kurebayashi J: Endocrine-resistant breast cancer: underlying mechanisms and strategies for overcoming resistance. Breast Cancer. 10:112–119. 2003. View Article : Google Scholar : PubMed/NCBI
7	Schiff R, Massarweh S, Shou J and Osborne CK: Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res. 9:447S–454S. 2003.PubMed/NCBI
8	Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE and Nicholson RI: Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology. 144:1032–1044. 2003. View Article : Google Scholar : PubMed/NCBI
9	Kim S, Lee J, Lee SK, Bae SY, Kim J, Kim M, Kil WH, Kim SW, Lee JE and Nam SJ: Protein kinase C-α downregulates estrogen receptor-α by suppressing c-Jun phosphorylation in estrogen receptor-positive breast cancer cells. Oncol Rep. 31:1423–1428. 2014.
10	Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM and Osborne CK: Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat. 24:85–95. 1992. View Article : Google Scholar
11	Li Z, Wang N, Fang J, Huang J, Tian F, Li C and Xie F: Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells. Oncol Rep. 27:1879–1886. 2012.PubMed/NCBI
12	Martin MB, Franke TF, Stoica GE, Chambon P, Katzenellenbogen BS, Stoica BA, McLemore MS, Olivo SE and Stoica A: A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology. 141:4503–4511. 2000.PubMed/NCBI
13	deFazio A, Chiew YE, McEvoy M, Watts CK and Sutherland RL: Antisense estrogen receptor RNA expression increases epidermal growth factor receptor gene expression in breast cancer cells. Cell Growth Differ. 8:903–911. 1997.PubMed/NCBI
14	Newby JC, Johnston SR, Smith IE and Dowsett M: Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer. Clin Cancer Res. 3:1643–1651. 1997.
15	Kenny PA, Lee GY, Myers CA, Neve RM, Semeiks JR, Spellman PT, Lorenz K, Lee EH, Barcellos-Hoff MH, Petersen OW, et al: The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol. 1:84–96. 2007. View Article : Google Scholar
16	Zhou C, Zhong Q, Rhodes LV, Townley I, Bratton MR, Zhang Q, Martin EC, Elliott S, Collins-Burow BM, Burow ME, et al: Proteomic analysis of acquired tamoxifen resistance in MCF-7 cells reveals expression signatures associated with enhanced migration. Breast Cancer Res. 14:R452012. View Article : Google Scholar : PubMed/NCBI
17	Borley AC, Hiscox S, Gee J, Smith C, Shaw V, Barrett-Lee P and Nicholson RI: Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells. Breast Cancer Res. 10:R1032008. View Article : Google Scholar : PubMed/NCBI
18	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 beta-catenin phosphorylation. Int J Cancer. 118:290–301. 2006. View Article : Google Scholar
19	Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, Wakeling AE and Nicholson RI: Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells. Breast Cancer Res Treat. 81:81–93. 2003. View Article : Google Scholar : PubMed/NCBI
20	Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT and Arteaga CL: Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res. 60:5887–5894. 2000.PubMed/NCBI
21	Jiang Y, Zhao X, Xiao Q, Liu Q, Ding K, Yu F, Zhang R, Zhu T and Ge G: Snail and Slug mediate tamoxifen resistance in breast cancer cells through activation of EGFR-ERK independent of epithelial-mesenchymal transition. J Mol Cell Biol. 6:352–354. 2014. View Article : Google Scholar : PubMed/NCBI
22	Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, et al: Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 64:3958–3965. 2004. View Article : Google Scholar : PubMed/NCBI
23	Sordella R, Bell DW, Haber DA and Settleman J: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 305:1163–1167. 2004. View Article : Google Scholar : PubMed/NCBI