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Abstract
Triple-negative breast cancer (TNBC) is often treated with anthracyclines (e.g., epirubicin or doxorubicin), but very little is known about anthracycline resistance, especially epirubicin resistance in TNBC. To identify novel long noncoding RNAs (lncRNAs) involved in epirubicin resistance in TNBC, we established a new TNBC MDA-MB-231 cell line that was resistant to epirubicin (Epi-R). A total of 12 differentially expressed lncRNAs were identified using RNA sequencing analysis of Epi-R cells. Among these lncRNAs, we found a novel intronic lncRNA, lnc005620, was highly expressed in Epi-R cells and human TNBC tissues. Further gain- and loss-of-function studies demonstrated that lnc005620 played an oncogenic role and partially abrogated the effects of epirubicin on TNBC cells. Using iTRAQ proteomics analysis, we found that three members of the integrin family, integrin β4, integrin β1 and integrin α6, were all upregulated in Epi-R MDA-MB-231 cells. Integrin β1, encoded by the ITGB1 gene, was validated to be a downstream target of lnc005620 in Epi-R MDA-MB-231 cells. Our study demonstrates that novel lnc005620 promotes TNBC progression and chemoresistance to epirubicin via integrin β1 both in vitro and in vivo and provides a promising therapeutic target for TNBC patients in terms of enhancing the benefits of epirubicin treatment.
Highlights
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women worldwide [1]
We demonstrated that epirubicin-resistant MDA-MB-231 cells showed elevated cell proliferation compared to the native controls (Figures 1A–C)
We found that knockdown of lnc005620 led to a decrease in proliferation of epirubicin-resistant MDA-MB-231 cells and this effect was more significant after treatment with 12.5 ng/ml epirubicin for 72 h (Figures 4B–D)
Summary
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women worldwide [1]. TNBC is usually more aggressive and associated with the development lnc005620 in Epirubicin Resistance of MDA-MB-231 Cells of resistance to conventional chemotherapeutics [2, 3]. Patients with TNBC experience worse prognosis and shorter overall survival owing to higher rates of recurrence, early metastasis and limited therapeutic options [4]. Anthracyclines (ANTs), including doxorubicin, epirubicin and idarubicin, are the main therapeutic drugs for TNBC [5]. Among ANTs, epirubicin is the most effective against TNBC, but 30–40% of patients still respond poorly, and acquired resistance has been reported [5, 9]. It is urgent to reveal the potential factors involved in regulating epirubicin resistance in TNBC and find useful therapeutic targets for patients
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