Abstract
Due to the lack of known therapeutic targets for triple-negative breast cancer (TNBC), chemotherapy is the only available pharmacological treatment. Pirarubicin (tetrahydropyranyl Adriamycin, THP) is the most commonly used anthracycline chemotherapy agent. However, TNBC has a high recurrence rate after chemotherapy, and the mechanisms of chemoresistance and recurrence are not entirely understood. To study the chemoresistance mechanisms, we first screened compounds on a pirarubicin-resistant cell line (MDA-MB-231R) derived from MDA-MB-231. The drug resistance index of MDA-MB-231R cells was approximately five times higher than that of MDA-MB-231 cells. MDA-MB-231R cells have higher GRP78 and lower miR-495-3p expression levels than MDA-MB-231 cells. Transfecting MDA-MB-231R cells with a siGRP78 plasmid reduced GRP78 expression, which restored pirarubicin sensitivity. Besides, transfecting MDA-MB-231R cells with miR-495-3p mimics increased miR-495-3p expression, which also reversed pirarubicin chemoresistance. Cell counting kit-8 (CCK-8), EdU, wound healing, and Transwell assays showed that the miR-495-3p mimics also inhibited cell proliferation and migration. Based on our results, miR-495-3p mimics could down-regulate GRP78 expression via the p-AKT/mTOR signaling pathway in TNBC cells. Remarkably, chemo-resistant and chemo-sensitive TNBC tissues had opposite trends in GRP78 and miR-495-3p expressions. The lower the GRP78 and the higher the miR-495-3p expression, the better prognosis in TNBC patients. Therefore, the mechanism of pirarubicin resistance might involve the miR-495-3p/GRP78/Akt axis, which would provide a possible strategy for treating TNBC.
Highlights
Breast cancer remains the leading cause of cancer-related mortality in women worldwide [1]
We developed the resistant MDA-MB-231R cell line in our laboratory (Xiangya Hospital, Central South University) by treating MDA-MB-231 cells with pirarubicin purchased from Zhejiang Haizheng Pharmaceutical Co., Ltd (Zhejiang, China)
Pirarubicin-resistant cells derived from pirarubicin-sensitive MDA-MB-231 cells
Summary
Breast cancer remains the leading cause of cancer-related mortality in women worldwide [1]. The term ‘triple-negative’ breast cancer (TNBC) was coined for cancers lacking detectable estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER-2) expression [2]. TNBC accounts for 15– 20% of all breast cancers [3]. Because of this lack of hormone receptors and HER-2 expression, the current TNBC treatment strategies are limited to chemotherapeutic agents, mainly anthracyclines and taxanes. Various targeting agents, such as anti-EGFR drugs, have been studied but have achieved limited success [4]. A considerable number of TNBC cases are resistant to chemotherapeutic agents, making them more aggressive and more likely to reoccur than other subtypes and resulting
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
