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Targeting HER3 with miR-450b-3p suppresses breast cancer cells proliferation.

ABSTRACT: In breast cancer cells, heterodimerization of HER2 and HER3 plays important and dominant roles in the functionality and transformation of HER-mediated pathways, in particular the PI3K/Akt survival pathway. HER3 was considered as a major signaling hub in HER2-amplified cancers. Inhibition of HER3 expression may therefore represent a rational therapeutic approach to breast cancers where HER2/HER3-mediated signaling plays a role in tumorigenesis and progression. miRNAs exerts important roles in regulating gene expressions by binding to and repressing target mRNAs. Here we reported that miRNA-450b-3p inhibits HER3 expression by directly targeting 3' UTR of HER3 mRNA and represses the downstream signal transductions of HER family. Overexpression of miRNA-450b-3p in SKBR3 cells inhibits cells clonogenic potential and enhances their sensitivity to trastuzumab, a monoclonal antibody that binds to the HER2 receptor, or doxorubicin through repressing proliferative signal pathways mediated by HER3/HER2/PI3K/AKT. Furthermore, we found that breast cancer patients with tumors that demonstrating upregulated HER3 (> 2-fold) and downregulated miR-450b-3p (> 2-fold) expressions compared with the paired adjacent non-tumorous tissues showed significantly poorer overall survival (P<0.05). Our study identified miRNA-450b-3p as a new tumor repressor and also provided some evidences suggesting that downregulation of miR-450b-3p expression with concurrent overexpression of HER3 may serve as a prognostic biomarker for poor overall survival in breast cancer patients.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC4130733 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Targeting HER3 with miR-450b-3p suppresses breast cancer cells proliferation.

Zhao Zhen Z Li Rui R Sha Sha S Wang Qiong Q Mao Weidong W Liu Tao T

Cancer biology & therapy 20140721 10

In breast cancer cells, heterodimerization of HER2 and HER3 plays important and dominant roles in the functionality and transformation of HER-mediated pathways, in particular the PI3K/Akt survival pathway. HER3 was considered as a major signaling hub in HER2-amplified cancers. Inhibition of HER3 expression may therefore represent a rational therapeutic approach to breast cancers where HER2/HER3-mediated signaling plays a role in tumorigenesis and progression. miRNAs exerts important roles in reg ...[more]

PMID: 25046105

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Project description:ObjectivesCircular RNA (circRNA) is a novel class of RNA, which exhibits powerful biological function in regulating cellular fate of various tumors. Previously, we had demonstrated that over-expression of circRNA circCDYL promoted progression of HER2-negative (HER2-) breast cancer via miR-1275-ULK1/ATG7-autophagic axis. However, the role of circCDYL in HER2-positive (HER2+) breast cancer, in particular its role in modulating cell proliferation, one of the most important characteristics of cellular fate, is unclear.Materials and methodsqRT-PCR and in situ hybridization analyses were performed to examine the expression of circCDYL and miR-92b-3p in breast cancer tissues or cell lines. The biological function of circCDYL and miR-92b-3p were assessed by plate colony formation and cell viability assays and orthotopic animal models. In mechanistic study, circRNAs pull-down, RNA immunoprecipitation, dual luciferase report, western blot, immunohistochemical and immunofluorescence staining assays were performed.ResultsCircCDYL was high-expressed in HER2+ breast cancer tissue, similar with that in HER2- breast cancer tissue. Silencing HER2 gene had no effect on expression of circCDYL in HER2+ breast cancer cells. Over-expression of circCDYL promoted proliferation of HER2+ breast cancer cells but not through miR-1275-ULK1/ATG7-autophagic axis. CircRNA pull down and miRNA deep-sequencing demonstrated the binding of miR-92b-3p and circCDYL. Interestingly, circCDYL did not act as miR-92b-3p sponge, but was degraded in miR-92b-3p-dependent silencing manner. Clinically, expression of circCDYL and miR-92b-3p was associated with clinical outcome of HER2+ breast cancer patients.ConclusionMiR-92b-3p-dependent cleavage of circCDYL was an essential mechanism in regulating cell proliferation of HER2+ breast cancer cells. CircCDYL was proved to be a potential therapeutic target for HER2+ breast cancer, and both circCDYL and miR-92b-3p might be potential biomarkers in predicting clinical outcome of HER2+ breast cancer patients.

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Targeting HER3 with miR-450b-3p suppresses breast cancer cells proliferation.

Publications

Targeting HER3 with miR-450b-3p suppresses breast cancer cells proliferation.

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