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Overexpression of miRNA-3613-3p Enhances the Sensitivity of Triple Negative Breast Cancer to CDK4/6 Inhibitor Palbociclib.

ABSTRACT: Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen and progesterone receptors and HER2, which are common therapeutic targets. CDK4/6 inhibitor Palbociclib has been approved as an anti-cancer agent for breast cancer. However, identifying biomarkers that predict the response to Palbociclib has always been a challenge for molecular targeted therapy. In this study, we identify microRNA as a hallmark in TNBC patients and explore if miR-3613-3p might serve as a tumor suppressor biomarker for triple negative breast cancer patients and if overexpression of miR-3613-3p could enhance the sensitivity of TNBC cells to Palbociclib. We show that the expression of miR3613-3p was down-regulated in TNBC tumors and cells, and the overexpression of miR-3613-3p in patients' tumor tissues was clinically and pathologically correlated with favorable prognosis, such as smaller tumor size and the lower Ki-67. In vitro, overexpression of miR-3613-3p inhibited cell proliferation, induced G1 cell-cycle arrest, and enhanced the sensitivity of TNBC cells to Palbociclib treatment. In vivo study revealed that overexpression of miR-3613-3p inhibited TNBC tumorigenesis and exerted a significant inhibitory effect of Palbociclib on MDA-MB-231 cells. Mechanically, SMAD2 and EZH2 were found to be two direct targets of miR-3613-3p and mediate the proliferation of TNBC cells and the sensitivity of the cells to Palbociclib through inducing cellular senescence. Our findings suggested that miR-3613-3p acts as a cancer-suppressor miRNA in TNBC. Moreover, our study showed that miR-3613-3p might be used as a predictive biomarker for the response of TNBC to Palbociclib.

SUBMITTER: Yu Y

PROVIDER: S-EPMC7729088 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Overexpression of miRNA-3613-3p Enhances the Sensitivity of Triple Negative Breast Cancer to CDK4/6 Inhibitor Palbociclib.

Yu Yuanhang Y Liao Han H Xie Rong R Zhang Yue Y Zheng Renjing R Chen Jianying J Zhang Bo B

Frontiers in oncology 20201127

Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen and progesterone receptors and HER2, which are common therapeutic targets. CDK4/6 inhibitor Palbociclib has been approved as an anti-cancer agent for breast cancer. However, identifying biomarkers that predict the response to Palbociclib has always been a challenge for molecular targeted therapy. In this study, we identify microRNA as a hallmark in TNBC patients and explore if miR-3613-3p might serve as a ...[more]

PMID: 33330073

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Project description:Background:Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks sensitivity to chemotherapy, endocrine therapy or targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been shown to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Therefore, we investigated whether the CDK4/6 inhibitor palbociclib (PD) could enhance the effects of cisplatin (CDDP) on TNBC. Methods:The effects of different drug regimens consisting of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and in vivo. MDA-MB-468 and RB-overexpressing MDA-MB-468 cells were used to assess the effect of the PD-CDDP regimens in vitro. Immunoblotting illustrated the role of the cyclin D1/RB/E2F axis signalling pathway. Results:PD induced G1 phase cell cycle arrest in the MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24 h, treatment with PD for 24 h followed by CDDP and treatment with CDDP for 24 h followed by PD had no influence on MDA-MB-231 cell apoptosis. We further investigated the effect of PD or CDDP withdrawal on the effects of sequential treatment and found that PD treatment for 48 h followed by withdrawal for 48 h and subsequent CDDP treatment (PD-CDDP) significantly increased apoptosis and inhibited the cell viability and colony formation of MDA-MB-231 cells, while with other regimens, PD and CDDP had an additive or antagonistic response. The preferential use of PD increased DNA damage induced by CDDP, as measured through ?H2AX immunofluorescence. These findings were not observed in sh-MDA-MB-231 cells, and experiments to assess cell function in MDA-MB-468 and RB-overexpressing MDA-MB-468 cells yielded similar results, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in an RB-dependent manner. In vivo, compared with single drug treatment, combination treatment inhibited tumour growth and Ki-67 expression in MDA-MB-231 xenograft models. Western blot analysis revealed that PD enhanced sensitivity to CDDP through the CDK4/6-cyclin D1-RB-E2F pathway. Conclusions:Pre-treatment with PD synchronized the tumour cell cycle through the CDK4/6-cyclin D1-RB-E2F pathway, which increased the antitumour effect of CDDP. Thus, PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

Project description:BACKGROUND:Glioblastoma (GBM) is the most common primary tumor in the brain, and the median survival time for GBM patients is only about 14 months; therefore, there is an urgent need for new and more effective strategies. Since cell cycle disorder is a key factor in tumor progression and immortalization, there is great potential for controlling cell cycle disorders in tumor cells in GBM patients. We began to study a novel combination of AQB and palbociclib to evaluate its potential as a new therapeutic target. METHODS:Protein mass spectrometry was used to identify the tumor suppressor genes up-regulated by AQB.The effects of HOTAIR - EZH2 inhibitor AQB and CDK4/6 inhibitor Palbociclib on glioma cells lines were examined in vitro and in vivo experiments. RESULTS:The combination of AQB and palbociclib inhibitors has a more pronounced suppression effect on the cell cycle, especially gliomas with high expression of HOTAIR and EZH2 and low expression of CWF19L1. We performed protein mass spectrometry to identify AQB upregulated tumor suppressor genes and confirmed that CWF19L1 is regulated by H3K27ac through chromatin immunoprecipitation-quantitative PCR results. Univariate and multivariate Cox regression analysis and database analysis were performed to suggest CWF19L1 is a good prognostic factor. Our experimental results suggested that CWF19L1 can be significantly upregulated by AQB and lead to degradation of CDK4/6, resulting in G1 arrest. The combination of AQB and CDK4/6 inhibitor palbociclib is more effective in inhibiting the growth of glioma than in the single drug, both in vivo and in vitro. Similarly, we found that both AQB and palbociclib can inhibit Wnt/?-catenin signaling, and the combined use of the two inhibitors has a stronger inhibitory effect on tumor metastasis. CONCLUSIONS:The combination of AQB and CDK4/6 inhibitor palbociclib has been found to have significant antitumor effects, which is likely to become a new strategy for glioma treatment.

Dataset Information

Overexpression of miRNA-3613-3p Enhances the Sensitivity of Triple Negative Breast Cancer to CDK4/6 Inhibitor Palbociclib.

Publications

Overexpression of miRNA-3613-3p Enhances the Sensitivity of Triple Negative Breast Cancer to CDK4/6 Inhibitor Palbociclib.

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