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UM171 suppresses breast cancer progression by inducing KLF2
Xiaojuan Ran1, Anling Hu2,3, Yi Kuang2,3
1Guizhou University of Traditional Chinese Medicine, Guiyang, China.
Purpose:
Breast cancer is the most frequent cancer in women with significant death rate. Morbidity is associated with drug resistance and metastasis. Development of novel drugs is unmet need. The aim of this study is to show potent anti-neoplastic activity of the UM171 compound on breast cancer cells and its mechanism of action.
Methods:
The inhibitory effect of UM171 on several breast cancer (BC) cell lines was examined using MTT and colony-forming assays. Cell cycle and apoptosis assays were utilized to determine the effect of UM171 on BC cell proliferation and survival. Wound healing scratch and transwell migration assays were used to examine the migration of BC cell lines in culture. Xenograft of mouse model with 4T1 cells was used to determine inhibitory effect of UM171 in vivo. Q-RT-PCR and western blotting were used to determine the expression level of genes effected by UM171. Lentivirus-mediated shRNAs were used to knockdown the expression of KLF2 in BC cells.
Results:
UM171 was previously identified as a potent agonist of human hematopoietic stem cell renewal and inhibitor of leukemia. In this study, UM171 was shown to inhibit the growth of multiple breast cancer cell lines in culture. UM171-mediated growth inhibition was associated with the induction of apoptosis, G2/M cell cycle arrest, lower colony-forming capacity, and reduced motility. In a xenotransplantation model of mouse triple-negative breast cancer 4T1 cells injected into syngeneic BALB/c mice, UM171 strongly inhibited tumor growth at a level comparable to control paclitaxel. UM171 increased the expression of the three PIM genes (PIM1-3) in breast cancer cells. Moreover, UM171 strongly induced the expression of the tumor suppressor gene KLF2 and cell cycle inhibitor P21CIP1. Accordingly, knockdown of KLF2 using lentivirus-mediated shRNA significantly attenuated the growth suppressor activity of UM171. As PIM1-3 act as oncogenes and are involved in breast cancer progression, induction of these kinases likely impedes the inhibitory effect of KLF2 induction by UM171. Accordingly, combination of UM171 with a PAN-PIM inhibitor LGH447 significantly reduced tumor growth in culture.
Conclusion:
These results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer.
Insights
The compound UM171 effectively inhibits breast cancer growth by inducing apoptosis and cell cycle arrest. Combining UM171 with a PIM inhibitor shows promise for treating aggressive breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer remains a leading cause of mortality in women, often driven by drug resistance and metastasis.
- Novel therapeutic strategies are urgently needed to combat aggressive breast cancer subtypes.
- The compound UM171 has shown potential as an anti-neoplastic agent against breast cancer cells.
Purpose of the Study:
- To evaluate the anti-neoplastic activity of UM171 against various breast cancer cell lines.
- To elucidate the mechanism of action underlying UM171's effects on breast cancer progression.
- To assess the efficacy of UM171 in preclinical models of breast cancer.
Main Methods:
- In vitro assays including MTT, colony-forming, cell cycle, apoptosis, wound healing, and transwell migration assays were used.
- In vivo efficacy was evaluated using a 4T1 triple-negative breast cancer xenograft mouse model.
- Gene expression analysis (Q-RT-PCR, Western blotting) and gene knockdown (shRNA) were employed to investigate molecular mechanisms.
Main Results:
- UM171 significantly inhibited breast cancer cell growth, proliferation, and migration in vitro.
- UM171 induced apoptosis and G2/M cell cycle arrest, and reduced colony formation.
- In vivo, UM171 demonstrated potent tumor growth inhibition comparable to paclitaxel, and modulated KLF2, P21, and PIM gene expression.
Conclusions:
- UM171 exhibits significant anti-cancer effects in breast cancer models, partly through KLF2 and P21 activation.
- Combination therapy with UM171 and a PAN-PIM inhibitor presents a novel therapeutic approach for aggressive breast cancer.
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