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Cancer Res. 2018 Sep 1;78(17):4915-4928. doi: 10.1158/0008-5472.CAN-18-0069. Epub 2018 Jun 26.

Loss of Estrogen-Regulated MIR135A1 at 3p21.1 Promotes Tamoxifen Resistance in Breast Cancer.

Author information

1
Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
2
Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore.
3
Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences and Institute of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
4
Department of Pathology, Anhui Medical University, Hefei, Anhui, China.
5
Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore. zhut@ustc.edu.cn pelobie@sz.tsinghua.edu.cn.
6
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, China.
7
Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China. zhut@ustc.edu.cn pelobie@sz.tsinghua.edu.cn.
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Contributed equally

Abstract

The dysregulation of miRNAs has been increasingly recognized as a critical mediator of cancer development and progression. Here, we show that frequent deletion of the MIR135A1 locus is associated with poor prognosis in primary breast cancer. Forced expression of miR-135a decreased breast cancer progression, while inhibition of miR-135a with a specific miRNA sponge elicited opposing effects, suggestive of a tumor suppressive role of miR-135a in breast cancer. Estrogen receptor alpha (ERα) bound the promoter of MIR135A1 for its transcriptional activation, whereas tamoxifen treatment inhibited expression of miR-135a in ERα+ breast cancer cells. miR-135a directly targeted ESR1, ESRRA, and NCOA1, forming a negative feedback loop to inhibit ERα signaling. This regulatory feedback between miR-135a and ERα demonstrated that miR-135a regulated the response to tamoxifen. The tamoxifen-mediated decrease in miR-135a expression increased the expression of miR-135a targets to reduce tamoxifen sensitivity. Consistently, miR-135a expression was downregulated in ERα+ breast cancer cells with acquired tamoxifen resistance, while forced expression of miR-135a partially resensitized these cells to tamoxifen. Tamoxifen resistance mediated by the loss of miR-135a was shown to be partially dependent on the activation of the ERK1/2 and AKT pathways by miR-135a-targeted genes. Taken together, these results indicate that deletion of the MIR135A1 locus and decreased miR-135a expression promote ERα+ breast cancer progression and tamoxifen resistance.Significance: Loss of miR-135a in breast cancer disrupts an estrogen receptor-induced negative feedback loop, perpetuating disease progression and resistance to therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4915/F1.large.jpg Cancer Res; 78(17); 4915-28. ©2018 AACR.

PMID:
29945962
DOI:
10.1158/0008-5472.CAN-18-0069
[Indexed for MEDLINE]
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