Abstract
The key barrier to the effectiveness of radiotherapy remains the radioresistance of breast cancer cells, resulting in increased tumor recurrence and metastasis. Thus, in this study, we aimed to clarify the difference between radiotherapy-resistant (RT-R) breast cancer (BC) and BC, and accordingly, analyzed gene expression levels between radiotherapy-resistant (RT-R) MDA-MB-231 cells and MDA-MB-231 cells. Gene expression array showed that ESM-1 was the most upregulated in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells. Then, we aimed to investigate the role of ESM-1 in the increased tumorigenesis of RT-R-BC cells. RT-R-MDA-MB-231, which showed an increased expression level of ESM1, exhibited significantly enhanced proliferation, colony forming ability, migration, and invasion compared to MDA-MB-231 cells, and ESM-1 knockdown effectively reversed these effects. In addition, compared to MDA-MB-231 cells, RT-R-MDA-MB-231 cells displayed improved adhesion to endothelial cells (ECs) due to the induction of adhesion molecules and increased MMP-9 activity and VEGF-A production, which were decreased by ESM-1 knockdown. Moreover, the expression of HIF-1α and activation of NF-κB and STAT-3 were increased in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells, and these effects were abolished by the knockdown of ESM-1. Finally, we confirmed the role of ESM-1 in tumorigenesis in an in vivo mouse model. Tumor volume, lung metastasis, and tumorigenic molecules (VEGF-A, HIF-1α, MMP-9, ICAM-1, VCAM-1, and phospho-NF-κB and phospho-STAT-3) were significantly induced in mice injected with ESM-1-overexpressing 4T1 cells and greatly enhanced in those injected with ESM-1-overexpressing RT-R-4T1 cells. Taken together, these results suggest for the first time that ESM-1 plays a critical role in tumorigenesis of breast cancer cells, especially RT-R-breast cancer cells, through the induction of cell proliferation and invasion.
Highlights
Breast cancer (BC) is the most common cancer diagnosed in women worldwide
These results suggest for the first time that endothelial cell specific molecule-1 (ESM-1) plays a critical role in tumorigenesis of breast cancer cells, especially RT-R-breast cancer cells, through the induction of cell proliferation and invasion
We found that RT-R-MDA-MB-231 cells, which are derived from highly metastatic MDA-MB-231 cells, showed most radio- and chemo-resistance of tested three cell lines (RT-R-MDA-MB-231, RT-R-MCF-7, and RT-R-T47D) and more increased protein levels of cancer stem cells (CSCs) markers CD44, Notch-4, Oct3/4, and ALDH1, compared to other RT-R-BC cells
Summary
Breast cancer (BC) is the most common cancer diagnosed in women worldwide. BC incidence is relatively high in North American and Western European women, but the incidence and mortality rates in Asian populations and low-income countries have been steadily increasing due to a lack of diagnostic and treatment programs [1,2]. Triple negative breast cancer (TNBC) is a Cancers 2020, 12, 1363; doi:10.3390/cancers12061363 www.mdpi.com/journal/cancers. Cancers 2020, 12, 1363 subtype of BC characterized by a lack of estrogen and progesterone receptors (ER/PR) expression and epidermal growth factor receptor 2 (HER2) expression. TNBC patients do not benefit from hormonal therapy due to the lack of receptor expression. Even though therapeutic methods including surgery, chemotherapy, and radiotherapy have been developed to treat cancer, TNBC patients develop therapeutic resistance and disease recurrence [3]. Radiotherapy (RT) is a method mostly used to treat solid cancers. RT has improved the lives of BC patients, some patients still develop tumor recurrence after completion of RT
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