Li Yan, Zhou Yidong, Mao Feng, Shen Songjie, Zhao Bin, Xu Yali, Lin Yan, Zhang Xiaohui, Cao Xi, Xu Ying, Chen Chang, Zhang Jinqian, Sun Qiang
Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Department of Laboratory Medicine and Central Laboratories, Guangdong Second Provincial General Hospital, Guangzhou, China.
Front Oncol. 2020 Aug 26;10:1509. doi: 10.3389/fonc.2020.01509. eCollection 2020.
The breast epithelial cells in patients with triple-negative breast cancer (TNBC) actually have specific estrogen receptor (ER) expression, and the abnormal glycosylation of UGT1A1 in TNBC cells resulted in abnormal expression and function of ERα through regulating the modification of ERα. Therefore, our study targets the role of UGT1A1 expression, then glycosylation modification of ERα (estrogen receptor α) and estrogen resistance in development of TNBC. The differential expression of mRNA and miRNA in TNBC tissues was tested. Luciferase activity was analyzed in TNBC cells treated with miR-452. Moreover, the human mammary gland and TNBC cell lines were dealt with estrogen and miR-452 or its inhibitors, then proliferation ability was further determined. Moreover, the role of interaction between UGT1A1 and ERα in the glycosylation modification of ERα and UGT activity, and metabolism of estrogen were assessed. The effects of miR-452 on TNBC by improving abnormal glycosylation modification of ERα by targeting UGT1A1 and estrogen resistance were studied and . The expression level of UGT1A1 in TNBC tumor tissues was higher than its matched para-tumorous tissues, but the miR-452 expression was opposite. The glycosylation modification site of ERα expressed in TNBC cells was different from that of normal mammary epithelial cells. The estrogen 17β-estradiol (E2) significantly promoted mitotic entry of TNBC cells. The interaction between UGT1A1 and ERα affected the expression level of each other, as well as the UGT enzyme activity and proliferation of TNBC cells. UGT1A1 induced production of intracellular estrogens and TNBC proliferation, but it could be reversed by overexpression of ERα. Upregulation of ERα caused the downregulation of UGT1A1 and marked decrease of intracellular estrogen products, and then suppressed TNBC proliferation. Moreover, UGT1A1 was the target gene of miR-452; miR-452 antagomir restrained TNBC xenograft. Our results demonstrated that estrogen was a positive factor in the proliferation of TNBC cells at onset of mitosis through accentuating the expression and enzyme activity of UGT1A1. However, miR-452 targeted to UGT1A1, then regulated glycosylation modification of ERα, estrogen metabolism, and TNBC development associated with estrogen resistance.
三阴性乳腺癌（TNBC）患者的乳腺上皮细胞实际上具有特定的雌激素受体（ER）表达，TNBC细胞中UGT1A1的异常糖基化通过调节ERα的修饰导致ERα表达和功能异常。因此，我们的研究针对UGT1A1表达的作用，进而研究ERα（雌激素受体α）的糖基化修饰以及雌激素抵抗在TNBC发生发展中的作用。检测了TNBC组织中mRNA和miRNA的差异表达。分析了用miR - 452处理的TNBC细胞中的荧光素酶活性。此外，用人乳腺和TNBC细胞系分别用雌激素和miR - 452或其抑制剂处理，然后进一步测定增殖能力。此外，评估了UGT1A1与ERα之间的相互作用在ERα糖基化修饰、UGT活性以及雌激素代谢中的作用。研究了miR - 452通过靶向UGT1A1改善ERα异常糖基化修饰对TNBC及雌激素抵抗的影响。TNBC肿瘤组织中UGT1A1的表达水平高于其配对的癌旁组织，但miR - 452的表达情况则相反。TNBC细胞中表达的ERα糖基化修饰位点与正常乳腺上皮细胞不同。雌激素17β - 雌二醇（E2）显著促进TNBC细胞的有丝分裂进入。UGT1A1与ERα之间的相互作用影响彼此的表达水平，以及TNBC细胞的UGT酶活性和增殖。UGT1A1诱导细胞内雌激素产生并促进TNBC增殖，但ERα过表达可使其逆转。ERα上调导致UGT1A1下调以及细胞内雌激素产物显著减少，进而抑制TNBC增殖。此外，UGT1A1是miR - 452的靶基因；miR - 452拮抗剂可抑制TNBC异种移植。我们的结果表明，雌激素通过增强UGT1A1的表达和酶活性，在TNBC细胞有丝分裂开始时的增殖中是一个积极因素。然而，miR - 452靶向UGT1A1，进而调节ERα的糖基化修饰、雌激素代谢以及与雌激素抵抗相关的TNBC发展。
