Downregulation of LINC00894-002 Contributes to Tamoxifen Resistance by Enhancing the TGF-β Signaling Pathway

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Xiulei Zhang¹, Meiting Wang^2,3, Huihui Sun¹, Tao Zhu¹, and Xiangting Wang^1,4,a*

¹Department of Cell and Developmental Biology, School of Life Sciences, University of Science and Technology of China, 230026 Hefei, China

²College of Liren, Yanshan University, 066004 Qinhuangdao, China

³Department of Neurobiology and Biophysics, School of Life Sciences, University of Science and Technology of China, 230026 Hefei, China

⁴CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, 230026 Hefei, China

^* To whom correspondence should be addressed.

Received September 4, 2017; Revision received February 9, 2018

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Tamoxifen is a widely used personalized medicine for estrogen receptor (ER)-positive breast cancer, but approximately 30% of patients receiving the treatment relapse due to tamoxifen resistance (TamR). Recently, several reports have linked lncRNAs to cancer drug resistance. However, the role of lncRNAs in TamR is unclear. To identify TamR-related lncRNAs, we first used a bioinformatic approach to predict whether they have connection with known TamR-associated genes by starBase v2.0 and divided them into two groups. Group A contains lncRNAs that connect with known TamR genes and group B contains lncRNAs that show no predicted interaction. Among the 12 lncRNAs in group A, 58.3% of them are either up- or downregulated in MCF-7/TamR cells compared to the sensitive cells. In contrast, the expression levels of all group B lncRNAs are not changed in MCF-7/TamR cells. LINC00894-002 exhibits the most sophisticated network pattern and is the most downregulated lncRNA in MCF-7/TamR cells. Moreover, we find that LINC00894-002 is directly upregulated by ERα. Knocking down LINC00894-002 downregulates expression of miR-200a-3p and miR-200b-3p, upregulates the expression of TGF-β2 and ZEB1, and finally contributes to TamR. Herein, we report the first case of an inhibitory lncRNA against TamR through the miR-200-TGF-β2-ZEB1 signaling pathway.

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KEY WORDS: tamoxifen resistance, estrogen receptor, breast cancer, LINC00894-002, miR-200-TGF-β2-ZEB1

DOI: 10.1134/S0006297918050139

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