Gemcitabine treatment enhances HER2 expression in low HER2-expressing breast cancer cells and enhances the antitumor effects of trastuzumab emtansine

Kan,Shin; Koido,Shigeo; Okamoto,Masato; Hayashi,Kazumi; Ito,Masaki; Kamata,Yuko; Komita,Hideo; Ishidao,Takefumi; Nagasaki,Eijiro; Homma,Sadamu

doi:10.3892/or.2015.3974

Gemcitabine treatment enhances HER2 expression in low HER2-expressing breast cancer cells and enhances the antitumor effects of trastuzumab emtansine

Authors:
- Shin Kan
- Shigeo Koido
- Masato Okamoto
- Kazumi Hayashi
- Masaki Ito
- Yuko Kamata
- Hideo Komita
- Takefumi Ishidao
- Eijiro Nagasaki
- Sadamu Homma
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Affiliations: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan, Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Tokyo, Japan, Shimbashi Medical Checkup Office, Jikei University Hospital, Tokyo, Japan, Tella, Inc., Tokyo, Japan
Published online on: May 12, 2015 https://doi.org/10.3892/or.2015.3974
Pages: 504-510

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Abstract

Trastuzumab emtansine (T-DM1), trastuzumab-conjugated with a cytotoxic agent, has shown promising antitumor effects in breast cancer. Since a good therapeutic response using T-DM1 treatment requires high human epidermal growth factor receptor 2 (HER2) expression, breast cancers with low or no HER2 expression have not been used for T-DM1 treatment. The aim of the present study was to show that treatment of low HER2-expressing breast cancer cells with gemcitabine (GEM) enhanced HER2 expression using RT-qPCR, immunoblot and flow cytometric analysis. The results showed that GEM treatment significantly enhanced HER2 expression in MDA-MB-231, MCF7 and BT-20 breast cancer cells, while paclitaxel (PTX) treatment induced lower or no enhancement in HER2 expression. The expression of HER2 mRNA was also enhanced in GEM-treated MCF7 cells. Treatment with an inhibitor for nuclear factor-(NF)-κB suppressed GEM-induced HER2 upregulation, indicating that NF-κB activation by GEM may be associated with HER2 upregulation. T-DM1 binding to HER2 on MCF-7 cells was enhanced by GEM pretreatment and the combined treatment of GEM and T-DM1 synergistically inhibited the proliferation of MCF7 cells. Thus, the combined treatment with GEM and T-DM1 may be a promising therapeutic modality for low HER2‑expressing breast cancers, which was facilitated by the unique HER2-upregulating effect of GEM.

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1	Cancer statistics, World Cancer Research Fund International. http://www.wcrf.org/cancer_statistics/world_cancer_statistics.php. http://www.wcrf.org/cancer_statistics/cancer_facts/women-breast-cancer.php. Accessed: date?
2	Center for Cancer Control and Information Services, National Cancer Center, Japan. Vital Statistics Japan. Ministry of Health, Labour and Welfare; 2013
3	Hudis CA: Trastuzumab - mechanism of action and use in clinical practice. N Engl J Med. 357:39–51. 2007. View Article : Google Scholar : PubMed/NCBI
4	Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI
5	Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuire WL: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neuoncogene. Science. 235:177–182. 1987. View Article : Google Scholar : PubMed/NCBI
6	Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 344:783–792. 2001. View Article : Google Scholar : PubMed/NCBI
7	Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, et al: Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 19:2587–2595. 2001.PubMed/NCBI
8	Nahta R and Esteva FJ: Herceptin: Mechanisms of action and resistance. Cancer Lett. 232:123–138. 2006. View Article : Google Scholar : PubMed/NCBI
9	Nahta R, Yu D, Hung MC, Hortobagyi GN and Esteva FJ: Mechanisms of disease: Understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 3:269–280. 2006. View Article : Google Scholar : PubMed/NCBI
10	Lewis GD, Figari I, Fendly B, Wong WL, Carter P, Gorman C and Shepard HM: Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother. 37:255–263. 1993. View Article : Google Scholar : PubMed/NCBI
11	Burris HA III, Tibbitts J, Holden SN, Sliwkowski MX and Lewis Phillips GD: Trastuzumab emtansine (T-DM1): A novel agent for targeting HER2⁺ breast cancer. Clin Breast Cancer. 11:275–282. 2011. View Article : Google Scholar : PubMed/NCBI
12	LoRusso PM, Weiss D, Guardino E, Girish S and Sliwkowski MX: Trastuzumab emtansine: A unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 17:6437–6447. 2011. View Article : Google Scholar : PubMed/NCBI
13	Barok M, Joensuu H and Isola J: Trastuzumab emtansine: Mechanisms of action and drug resistance. Breast Cancer Res. 16:2092014. View Article : Google Scholar : PubMed/NCBI
14	Barok M, Tanner M, Köninki K and Isola J: Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res. 13:R462011. View Article : Google Scholar : PubMed/NCBI
15	Barok M, Tanner M, Köninki K and Isola J: Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett. 306:171–179. 2011. View Article : Google Scholar : PubMed/NCBI
16	Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, et al EMILIA Study Group: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 367:1783–1791. 2012. View Article : Google Scholar : PubMed/NCBI
17	Cox G, Vyberg M, Melgaard B, Askaa J, Oster A and O’Byrne KJ: Herceptest: HER2 expression and gene amplification in non-small cell lung cancer. Int J Cancer. 92:480–483. 2001. View Article : Google Scholar : PubMed/NCBI
18	Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, et al: College of American Pathologists: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med. 138:241–256. 2014. View Article : Google Scholar :
19	Dawood S, Broglio K, Buzdar AU, Hortobagyi GN and Giordano SH: Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: An institutional-based review. J Clin Oncol. 28:92–98. 2010. View Article : Google Scholar :
20	Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, et al: Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 26:3950–3957. 2008. View Article : Google Scholar : PubMed/NCBI
21	Aogi K, Yoshida M, Sagara Y, Kamigaki S, Okazaki M, Funai J, Fujimoto T, Toi M, Saeki T and Takashima S: The efficacy and safety of gemcitabine plus paclitaxel combination first-line therapy for Japanese patients with metastatic breast cancer including triple-negative phenotype. Cancer Chemother Pharmacol. 67:1007–1015. 2011. View Article : Google Scholar
22	Takahara A, Koido S, Ito M, Nagasaki E, Sagawa Y, Iwamoto T, Komita H, Ochi T, Fujiwara H, Yasukawa M, et al: Gemcitabine enhances Wilms’ tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response. Cancer Immunol Immunother. 60:1289–1297. 2011. View Article : Google Scholar : PubMed/NCBI
23	Hernández-Vargas H, Rodríguez-Pinilla SM, Julián-Tendero M, Sánchez-Rovira P, Cuevas C, Antón A, Ríos MJ, Palacios J and Moreno-Bueno G: Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 102:157–172. 2007. View Article : Google Scholar
24	Cao Y, Luo JL and Karin M: IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. Proc Natl Acad Sci USA. 104:15852–15857. 2007. View Article : Google Scholar : PubMed/NCBI
25	Cao N, Li S, Wang Z, Ahmed KM, Degnan ME, Fan M, Dynlacht JR and Li JJ: NF-kappaB-mediated HER2 overexpression in radiation-adaptive resistance. Radiat Res. 171:9–21. 2009. View Article : Google Scholar : PubMed/NCBI
26	Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ and Yarden Y: A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 16:5276–5287. 1996.PubMed/NCBI
27	Spector NL and Blackwell KL: Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 27:5838–5847. 2009. View Article : Google Scholar : PubMed/NCBI
28	O’Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O’Donovan N and Slamon DJ: Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 9:1489–1502. 2010. View Article : Google Scholar
29	Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature. 490:61–70. 2012. View Article : Google Scholar : PubMed/NCBI
30	Yoshida R, Tazawa H, Hashimoto Y, Yano S, Onishi T, Sasaki T, Shirakawa Y, Kishimoto H, Uno F, Nishizaki M, et al: Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells. Cancer Immunol Immunother. 61:1905–1916. 2012. View Article : Google Scholar : PubMed/NCBI
31	Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, Smith DJ, Landolfi S, Ramon y Cajal S, Arribas J, et al: Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 28:803–814. 2009. View Article : Google Scholar