A miR-20a/MAPK1/c-Myc regulatory feedback loop regulates breast carcinogenesis and chemoresistance.

Abstract

Chemoresistance often leads to the failure of breast cancer treatment. MicroRNAs (miRNAs) play an important role in the progression and chemoresistance of cancer. However, because of the complexity of the mechanisms of chemoresistance and the specificity of miRNA regulation in different cell types, the function of miR-20a in breast cancer chemoresistance is still unclear. Here, by using miRNA microarray and high-content screening techniques, we found that miR-20a/b were significantly downregulated in breast cancer tissues compared with normal breast tissues, and low miR-20a/b expression was correlated with poor survival in breast cancer patients. Ectopic overexpression of miR-20a sensitized breast cancer cells to a broad spectrum of chemotherapy drugs and suppress their proliferation both in vitro and in vivo. Further study demonstrated that miR-20a directly targeted the 3'untranslated region of MAPK1, and thus downregulated the expression of P-gp and c-Myc by inhibiting the MAPK/ERK signaling pathway, whereas c-Myc can bind to the promoter region of the miR-20a gene to promote the expression of miR-20a. Together, our study identified a novel miR-20a/MAPK1/c-Myc feedback loop that regulates breast cancer growth and chemoresistance. These findings suggest that miR-20a synergizing with anticancer drugs will be a promising treatment strategy, especially for chemoresistant patients.

• Authors: Wengong Si, Jiaying Shen, Chengyong Du, Danni Chen, Xidong Gu, Chenggong Li, Minya Yao, Jie Pan, Junchi Cheng, Donghai Jiang, Liang Xu, Chang Bao, Peifen Fu, Weimin Fan
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 25 Issue 2 Pg. 406-420 (02 2018) ISSN: 1476-5403 [Electronic] England
• PMID: 29125598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• MIRN20a microRNA, human
• MicroRNAs
• Proto-Oncogene Proteins c-myc
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Humans
• MicroRNAs (genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Oligonucleotide Array Sequence Analysis
• Proto-Oncogene Proteins c-myc (metabolism)
• Tumor Cells, Cultured