Inhibition of PIM1 attenuates the stem cell-like traits of breast cancer cells by promoting RUNX3 nuclear retention.

Hui Liu,Cheng Chen,Chenxi Xiang,Qing Li,Yubing Li,Dongshen Ma,Qianqian Yin

doi:10.1111/jcmm.15272

Abstract

Finding out the driver gene critical for the maintenance of breast cancer stem cells (BrCSCs) is important for designing a new strategy to eradicate these cells to improve patient's prognosis. Here, in our study, we revealed that PIM1, an oncogenic serine‐threonine kinase and a well‐proven contributor to the tumorigenesis of breast cancer, was involved in BrCSCs regulation and promised to be a new target for eradicating BrCSCs. In brief, PIM1 could enhance the stem cell–like traits of breast cancer cells by promoting the phosphorylation and cytoplasmic localization of RUNX3. The nuclear dislocation of RUNX3 disabled this tumour suppressor and led to breast cancer cells gaining stem cell–like traits. Inhibition of PIM1 significantly induced the nuclear retention of RUNX3, recovered its transcriptional function and attenuated the stem cell–like properties of breast cancer cells. Those findings deepened our understanding of PIM1's oncogenic effect, underlining the significance of PIM1 in designing a new strategy aimed at BrCSCs.

Highlights

Breast cancer is the most common cause of death in women worldwide
It was estimated that breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes, and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017.1 Even the mortality rate for breast cancer patients overall slowly declines with the improvement of early tumour detection and introduction of endocrine therapy in hormone receptor-positive breast cancer, and triple-negative breast cancer (TNBC) patients still hold the most dismal prognosis and more likely succumb to tumour relapse or metastasis, which usually lead to death
We demonstrated that PIM1 could phosphorylate RUNX3 to facilitate its cytoplasmic retention, suppressing the transcriptional activity of RUNX3 and promoting breast cancer to gain breast cancer stem cells (BrCSCs)-like traits

Summary

Introduction

Breast cancer is the most common cause of death in women worldwide. It was estimated that breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes, and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017.1 Even the mortality rate for breast cancer patients overall slowly declines with the improvement of early tumour detection and introduction of endocrine therapy in hormone receptor-positive breast cancer, and triple-negative breast cancer (TNBC) patients still hold the most dismal prognosis and more likely succumb to tumour relapse or metastasis, which usually lead to death. We revealed that inhibition of PIM1 kinase could attenuate the stem cell–like traits in breast cancer by rescuing the nuclear expression of RUNX3.

Results

Conclusion