Inhibitory effects of iron depletion plus eribulin on the breast cancer microenvironment

• Main Authors: Wataru Goto, Shinichiro Kashiwagi, Yuka Asano, Koji Takada, Tamami Morisaki, Katsuyuki Takahashi, Hisakazu Fujita, Masatsune Shibutani, Ryosuke Amano, Tsutomu Takashima, Shuhei Tomita, Kosei Hirakawa, Masaichi Ohira
• Format: Article
• Language: English
• Published: BMC 2020-12-01
• Series: BMC Cancer
• Subjects: Iron chelator; Eribulin mesylate; Breast cancer; Xenograft; Epithelial-mesenchymal transition; Immune checkpoints
• Online Access: https://doi.org/10.1186/s12885-020-07673-9

Abstract Background Iron is required for the proliferation of cancer cells, and its depletion suppresses tumor growth. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, disrupts the tumor microenvironment via vascular remodeling and obstruction of the epithelial-mesenchymal transition (EMT). Herein, we investigated the effects of the iron chelator on tumor-related properties of breast cancer cells and the effects of iron chelator plus eribulin on tumor growth in vivo. Methods Two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and BT-549, and one hormone-receptor positive breast cancer cell line, MCF-7, were used in our study. Cell proliferation, cell migration, cell cycle position, and gene expression were analyzed via MTT assays, wound-healing assays, flow cytometry, and quantitative real-time-polymerase chain reaction, respectively. For the in vivo experiments, mice with breast cancer xenografts were treated with the inhibitors, alone or together, and tumor volume was determined. Results Iron chelator inhibited breast cancer cell proliferation and decreased the proportion of S-phase cells. Conversely, it induced hypoxia, angiogenesis, EMT, and immune checkpoints, as determined by quantifying the expression of marker mRNAs in MDA-MB-231 and MCF-7 cells. Eribulin suppressed the expression of the hypoxia and EMT related marker mRNAs in the presence of iron chelator. Iron chelator plus eribulin inhibited tumor growth in vivo to a greater extent than did either inhibitor alone. Conclusions Although iron chelator induces oncogenic events (hypoxia, angiogenesis, EMT, and immune checkpoints), it may be an effective treatment for breast cancer when administered in combination with eribulin.