title: Gemcitabine treatment enhances HER2 expression in low HER2-expressing breast cancer cells and enhances the antitumor effects of trastuzumab emtansine.
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.
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kan
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koido
authors.affiliation: Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kamata
authors.affiliation: Shimbashi Medical Checkup Office, Jikei University Hospital, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Komita
authors.affiliation: Tella, Inc., Tokyo, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Ishidao
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Nagasaki
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Sadamu
authors.initials: S
authors.lastname: Homma
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000068878:Trastuzumab; D015854:Up-Regulation; D000093542:Gemcitabine
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D008453:Maytansine; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine; C508053:ERBB2 protein, human