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: Shin Kan, Shigeo Koido, Masato Okamoto, Kazumi Hayashi, Masaki Ito, Yuko Kamata, Hideo Komita, Takefumi Ishidao, Eijiro Nagasaki, Sadamu Homma
• Journal: Oncology reports (Oncol Rep) Vol. 34 Issue 1 Pg. 504-10 (Jul 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 25976081 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Deoxycytidine
• Maytansine
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab
• Paclitaxel
• Ado-Trastuzumab Emtansine
• Gemcitabine

Topics

• Ado-Trastuzumab Emtansine
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Synergism
• Female
• Humans
• MCF-7 Cells
• Maytansine (analogs & derivatives, pharmacology)
• Paclitaxel (pharmacology)
• Receptor, ErbB-2 (genetics, metabolism)
• Trastuzumab
• Up-Regulation
• Gemcitabine