Exosomal miRNA-205 promotes breast cancer chemoresistance and tumorigenesis through E2F1

Abstract

Breast cancer (BC) is a common malignant tumor in females. The challenge in treating BC is overcoming chemoresistance. Exosome-mediated transfer of miRNAs is a molecule-shuttle in intercellular communication. Thus, we aimed to investigate whether exosomal miRNA-205 could affect chemoresistance and tumorigenesis in recipient tumor cells and to elucidate the underlying mechanism in vivo and in vitro . Microarray and qRT-PCR assays demonstrated that miRNA-205 was upregulated in tamoxifen resistance MCF-7/TAMR-1 (M/T) cells and M/T cell-derived exosomes (M/T-Exo). The M/T-Exo was internalized by human BC cells (BCCs), causing increased expression of miRNA-205 in BCCs. Coculturing with M/T-Exo promoted tamoxifen resistance, proliferation, migration, and invasion while suppressed apoptosis in recipient BCCs, which were associated with activating the caspase pathway and phosphorylating Akt. Luciferase reporter assays showed that miRNA-205 directly targeted E2F Transcription Factor 1 (E2F1) in BCCs. Furthermore, knockdown of miRNA-205 or overexpression of E2F1 reversed the roles of M/T-Exo in BCCs. In vivo experiments showed that the intratumoral injection of M/T-Exo caused greater tamoxifen resistance and larger tumor size relative to mice treated with miRNA-205-knockdown or E2F1-overexpressing BCCs. Together, the results suggest that exosomal miRNA-205 may promote tamoxifen resistance and tumorigenesis in BC through targeting E2F1 in vivo and in vitro .

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

“…Exosomes are small vesicles secreted by cells that can mediate cell–cell signaling, and along with other molecules can also transport RNA molecules [ 97 ]. There are many reports on exosome-based cell-to-cell communication carried out by miRNAs that participate in the regulation of tumorigenesis and angiogenesis [ 16 , 98 , 99 , 100 , 101 ]. It is, therefore, reasonable to speculate that those pathways can also be regulated by vtRNA fragments secreted via exosomes.…”

Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer

“…Three miRNAs, miR-101, miR-206, and miR-24-3p, have been identified to significantly increase in breast cancer tissues, with their ectopic expression inducing tam resistance in cancer cells [ 23 , 24 , 25 ]. In another study, exosomal miR-205 that targets the E2F1 transcription factor, which is a major driving force for the cell cycle, has been shown to be dysregulated in breast cancer cells by promoting tam resistance [ 26 ]. Histone modifications can also contribute to tam resistance by affecting gene expression.…”

Advances of Exosomal miRNAs in Breast Cancer Progression and Diagnosis

“…Breast cancer patients' exosomes switch nontumorigenic epithelial cells into tumors in a Dicer-dependent manner [36]. Additionally, miRNA-205 affects breast cancer cells proliferation via targeting E2F1 [37].…”

“…In addition to screening the potential biomarkers, RT-qPCR can also help to explore the functions of exosomal miRNAs in the process of breast cancer. Zhao et al [37] verified exosomal miRNA-205 might promote drug resistance and tumorigenesis in breast cancer with the help of RT-qPCR. The source of exosomes in this article was a human breast cancer cell line.…”