A miR-26a/E2F7 feedback loop contributes to tamoxifen resistance in ER-positive breast cancer
A miR-26a/E2F7 feedback loop contributes to tamoxifen resistance in ER-positive breast cancer
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DOI：
10.3892/ijo.2018.4492
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发表时间：
2018-10-01
影响因子：
5.2
通讯作者：
Pang, Yamei
中科院分区：
文献类型：
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作者：
Liu, Jian;Li, Xiang;Pang, Yamei
他莫昔芬（TAM）耐药性是雌激素受体（ER）阳性乳腺癌治疗中的一个重大挑战。先前的研究已经揭示了microRNA (miRNA/miR)-26a在乳腺癌TAM耐药中的重要作用。然而，miR-26a对TAM耐药调控作用的机制仍有待阐明。采用逆转录-定量聚合酶链反应检测miR-26a在er阳性乳腺癌中的表达水平。western blotting检测E2F转录因子7 （E2F7）和MYC原癌基因bHLH转录因子（MYC）水平。本研究表明，与正常乳腺组织相比，miR-26a在er阳性乳腺癌中的表达降低，而E2F7的表达显著升高。此外，在er阳性乳腺癌中检测到miR-26a和E2F7表达呈负相关。结果表明，miR-26a通过翻译抑制直接抑制E2F7表达，部分通过抑制E2F7间接抑制MYC表达。反过来，E2F7通过myc诱导的mirna转录抑制降低了miR-26a的表达。此外，转染miR-26a模拟物增加了其宿主基因（CTD小磷酸酶样和CTD小磷酸酶2）的表达，而异位表达E2F7则消除了miR-26a的作用。这些发现表明，miR-26a和E2F7可能形成双负反馈回路，导致miR-26a在er阳性乳腺癌中下调，E2F7上调。miR-26a敲低和E2F7过表达都赋予MCF-7细胞对TAM的抗性。相反，miR-26a过表达和E2F7沉默使MCF-7耐药细胞对TAM重新敏感。这些发现表明miR-26a和E2F7之间的反馈回路可能促进er阳性乳腺癌的TAM耐药。
Tamoxifen (TAM) resistance is a substantial challenge in the treatment of estrogen receptor (ER)-positive breast cancer. Previous studies have revealed an important role of microRNA (miRNA/miR)-26a in TAM resistance in breast cancer. However, the mechanism underlying the regulatory effects of miR-26a on TAM resistance remains to be elucidated. The expression levels of miR-26a in ER-positive breast cancer were detected by reverse transcription-quantitative polymerase chain reaction. E2F transcription factor 7 (E2F7) and MYC proto-oncogene, bHLH transcription factor (MYC) levels were detected by western blotting. The present study demonstrated that miR-26a expression was reduced in ER-positive breast cancer compared with in normal breast tissues, whereas E2F7 expression was significantly elevated. Furthermore, an inverse correlation between miR-26a and E2F7 expression was detected in ER-positive breast cancer. The results indicated that miR-26a directly inhibited E2F7 expression through translational inhibition and indirectly inhibited MYC expression partly via E2F7 repression. E2F7, in turn, decreased miR-26a expression via MYC-induced transcriptional inhibition of miRNAs. Furthermore, transfection with miR-26a mimics increased the expression of its host genes (CTD small phosphatase like and CTD small phosphatase 2), whereas ectopic E2F7 expression abrogated the effects of miR-26a. These findings indicated that miR-26a and E2F7 may form a double-negative feedback loop, resulting in downregulation of miR-26a and upregulation of E2F7 in ER-positive breast cancer. Both miR-26a knockdown and E2F7 overexpression conferred resistance to TAM in MCF-7 cells. Conversely, miR-26a overexpression and E2F7 silencing resensitized MCF-7 resistant cells to TAM. These findings revealed that a feedback loop between miR-26a and E2F7 may promote TAM resistance in ER-positive breast cancer.