UM171 suppresses breast cancer progression by inducing KLF2
Purpose: Breast cancer is the most common cancer in women and has a high mortality rate, with drug resistance and metastasis being major contributors to its morbidity. There is a pressing need for novel therapeutic agents. This study aims to evaluate the potent anti-cancer effects of the compound UM171 on breast cancer cells and to elucidate its mechanism of action.
Methods: We assessed the inhibitory effects of UM171 on various breast cancer (BC) cell lines using MTT and colony-forming assays. Cell cycle and apoptosis assays were conducted to evaluate UM171’s impact on cell proliferation and survival. Migration assays, including wound healing scratch and transwell assays, were employed to analyze BC cell movement. In vivo effects were tested using a mouse xenograft model with 4T1 cells. Gene expression changes induced by UM171 were measured by Q-RT-PCR and western blotting. Lentivirus-mediated shRNAs were used to knock down KLF2 expression in BC cells.
Results: UM171, previously recognized as a potent agonist of human hematopoietic stem cell renewal and a leukemia inhibitor, was shown to effectively inhibit the growth of multiple breast cancer cell lines. This growth inhibition was linked to apoptosis induction, G2/M cell cycle arrest, reduced colony-forming ability, and diminished cell motility. In a mouse model of triple-negative breast cancer using 4T1 cells, UM171 significantly suppressed tumor growth, comparable to the effects of the control drug paclitaxel. UM171 increased the expression of PIM genes (PIM1-3) in breast cancer cells and strongly induced the expression of the tumor suppressor gene KLF2 and the cell cycle inhibitor P21CIP1. Knockdown of KLF2 using lentivirus-mediated shRNA notably reduced UM171’s growth-inhibitory effects. Since PIM1-3 are oncogenes involved in breast cancer progression, their induction may counteract KLF2’s inhibitory effects. Combination treatment with UM171 and the PAN-PIM inhibitor LGH447 significantly enhanced tumor growth suppression in culture.
Conclusion: UM171 inhibits breast cancer progression primarily through the activation of KLF2 and P21CIP1. Combining UM171 with a PAN-PIM inhibitor presents a promising new therapeutic approach for aggressive breast cancer.