miR-452 Reverses Abnormal Glycosylation Modification of ERα and Estrogen Resistance in TNBC (Triple-Negative Breast Cancer) Through Targeting UGT1A1

Abstract

Background: 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. Methods: 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 in vitro and in vivo. Results: 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. Li et al. miR-452 Reverses TNBC Estrogen Resistance Conclusion: 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.

LINC01140 Targeting miR-452-5p/RGS2 Pathway to Attenuate Breast Cancer Tumorigenesis

“…The researchers also reported the inhibitory influence of miR-452 antagonists on TNBC xenografts. Herein, my findings show high expressions of miR-452-5p in BC, which is similar to the next-generation sequencing results of Li et al [35], but contrary to the results of RT-qPCR detection. Nevertheless, it is speculated that the difference in the aggressiveness of the cancer tissue may be responsible for this.…”

“…MiR-9 levels may be used as a potential noninvasive tumor marker for BC [ 34 ]. Li et al [ 35 ] reported that the results of the next-generation sequencing showed the overexpression of miR-452 BC tissues. Meanwhile, their RT-qPCR results revealed the low levels of miR-452 levels in TNBC.…”

“…Cumulative studies have documented abnormal miRNA cluster expressions in BC, showing protumor and antitumor effects [ 32 ]. In future studies, I may explore the effects of miR-452 clusters on BC, based on the report of Li et al [ 35 ]. Furthermore, the downstream signaling pathway of the LINC01140/miR-452-5p/RGS2 axis is also worth investigating.…”

MicroRNAs as a clue to overcome breast cancer treatment resistance

“…UGT1A1 induced abnormal glycosylation in ERα and decreased its expression. Restoring the miR-452 expression in TNBC cells, the expression and function of UGT1A1 were reverted [156] leading to a rise in ERα expression that is essential to sensitize the cells to TAM [157]. miR-135a is another miRNA related to TAM resistance in BC.…”

Concanavalin A inhibits human liver cancer cell migration by regulating F‑actin redistribution and assembly via MAPK signaling pathway

“…Their malignant capacity usually derives from abnormal function of mutant oncoproteins and aberrant signal transduction ( 1 ). Under abnormal molecular signal transmission, certain functional proteins would be modified by incorrect glycosylation under the action of the Golgi apparatus, and this abnormal glycosylation is closely associated with the malignant proliferation of tumor cells ( 2 , 3 ). Moreover, aberrant glycosylation of functionally membrane glycoproteins would affect adhesion or motility of tumor cells, resulting in invasion and metastasis.…”