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

• Published in: Oncology reports Vol. 34; no. 1; pp. 504 - 510
• Main Authors: KAN, SHIN, KOIDO, SHIGEO, OKAMOTO, MASATO, HAYASHI, KAZUMI, ITO, MASAKI, KAMATA, YUKO, KOMITA, HIDEO, ISHIDAO, TAKEFUMI, NAGASAKI, EIJIRO, HOMMA, SADAMU
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.07.2015; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; combination therapy; Cytotoxicity; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Dosage and administration; Drug Synergism; Drug therapy; Female; Gemcitabine; Gene amplification; Gene expression; Health aspects; human epidermal growth factor receptor 2; Humans; Immunotherapy; Kinases; Maytansine - analogs & derivatives; Maytansine - pharmacology; MCF-7 Cells; Metastasis; Monoclonal antibodies; Mutation; Oncology, Experimental; paclitaxel; Paclitaxel - pharmacology; Pancreatic cancer; Polymerization; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Targeted cancer therapy; Trastuzumab; trastuzumab emtansine; Up-Regulation; Japan
• ISSN: 1021-335X; 1791-2431; 1791-2431
• DOI: 10.3892/or.2015.3974

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.