Breast cancer is the most common cancer in women and its metastasis markedly exacerbates patients’ prognosis. In particular, triple negative breast cancer (TNBC), which lacks estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2), is an aggressive subtype of breast cancer frequently forming metastatic lesions. Differentiation-inducing factor-1 (DIF-1) identified in Dictyostelium discoideum inhibits cell proliferation and migration of various mammalian cancer cells. However, the effect of DIF-1 on TNBC has not been examined. Here, we investigated whether DIF-1 shows anti-proliferative and anti-metastatic effects on TNBC by in-vivo and in-vitro experiments.
In in-vivo experiments, we used cancer xenograft model mice in which murine TNBC 4T1/Luc cells (1.0 × 106 cells/mL) were injected into mammary fat pads to evaluate the effects of intragastric administration of DIF-1 (300 mg/kg/day) on the primary tumor growth and lung metastasis. In in-vitro experiments, we carried out assays for cell proliferation, migration and invasion to evaluate the anti-proliferative and anti-metastatic effects of DIF-1. We also conducted Western blotting and real-time RT-PCR to identify the mechanisms for DIF-1’s anti-cancer effects.
In vivo, administration of DIF-1 significantly suppressed the primary tumor growth and lung metastasis without adverse effects such as weight loss and myelosuppression. In vitro, DIF-1 reduced cyclin D1 and c-Myc by inhibiting transcription and promoting degradation of the proteins, which resulted in the suppression of cell proliferation. DIF-1 also suppressed cell migration and invasion and reduced the protein expressions of snail, twist, vimentin and MMP-2, crucial factors in epithelial-mesenchymal transition (EMT).
DIF-1 exerts anti-cancer effects in TNBC by reducing cell cycle accelerators and reversing EMT. Our findings suggest that using DIF-1 as a lead compound could develop a novel anti-cancer agent for TNBC.
The study protocol was approved by the Committee on Ethics of Animal Experiments of Kyushu University. Animal handling and procedures were carried out in compliance with the Guidelines for Animal Experiments, Kyushu University, and the Law (No. 105) and Notification (No. 6) of the Japanese Government.
Has not received any funding.
All authors have declared no conflicts of interest.