Journal
ONCOGENE
Volume 32, Issue 9, Pages 1173-1182Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.128
Keywords
microRNAs; tamoxifen resistance; epithelial-mesenchymal transition; breast cancer; metadherin
Funding
- National Genome Research Network [01GS0864]
- German Federal Ministry of Education and Research (BMBF)
- Wilhelm Sanderstiftung [2009.051.1]
- DKFZ International PhD Program
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Epithelial-mesenchynnal transition (EMT) is an initiating event in tumor cell invasion and metastasis. It has been shown to occur in resistance to a range of cancer therapies, including tamoxifen. MicroRNAs (miRNAs) have been associated with EMT as well as resistance to standard therapies. To investigate the role of nniRNAs in the development of resistance to tamoxifen as well as accompanying EMT-like properties, we established a tamoxifen-resistant (TamR) model by continually exposing MCF-7 breast cancer cells to tamoxifen. In addition to the molecular changes known to be involved in acquired tamoxifen resistance, TamR cells displayed nnesenchymal features and had increased invasiveness. Genome-wide miRNA microarray analysis revealed that miRNA-375 was among the top downregulated miRNAs in resistant cells. Re-expression of miR-375 was sufficient to sensitize TamR cells to tamoxifen and partly reversed EMT. A combination of mRNA profiling, bioinformatics analysis and experimental validation identified metadherin (MTDH) as a direct target of miR-375. Knockdown of MTDH partially phenocopied the effects of miR-375 on the sensitivity to tamoxifen and the reversal of EMT. We observed an inverse correlation between the expression of miR-375 and its target MTDH in primary breast cancer samples, implying the pathological relevance of targeting. Finally, tamoxifen-treated patients with higher expression of MTDH had a shorter disease-free survival and higher risk of relapse. As most cancer-related deaths occur because of resistance to standard therapies and metastasis, re-expression of miR-375 or targeting MTDH might serve as potential therapeutic approaches for the treatment of TamR breast cancer. Oncogene (2013) 32, 1173-1182; doi:10.1038/onc.2012.128; published online 16 April 2012
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