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CCDC170 affects breast cancer apoptosis through IRE1 pathway.

ABSTRACT: Genome-wide association studies have revealed that multiple single-nucleotide polymorphisms in the intergenic region between estrogen receptor 1 and coiled-coil domain containing 170 (CCDC170) are associated with breast cancer risk. We performed microarray and bioinformatics analyses to identify genes that were induced upon CCDC170 overexpression, and confirmed our findings by evaluating paraffin-embedded breast cancer tissues and conducting cellular assays. In CCDC170-overexpressing MCF7 breast cancer cells, microarray analyses revealed that inositol-requiring enzyme 1 (IRE1) was the most elevated gene in enriched pathways. In breast cancer tissues, IRE1 expression correlated positively with CCDC170 and X-box binding protein 1 expression at both the mRNA and protein levels. In a survival analysis, patients with higher CCDC170 levels exhibited better disease-free survival. Western blotting indicated that overexpressing CCDC170 in MCF7 cells increased protein levels of IRE1?, estrogen receptor ? and X-box binding protein 1, while silencing CCDC170 reduced them. CCDC170 overexpression promoted apoptosis in MCF7 cells, and this effect was more obvious under endoplasmic reticulum stress. MCF7 cells overexpressing CCDC170 were more sensitive to paclitaxel. Our study showed that higher CCDC170 expression is associated with a better prognosis in breast cancer patients and that CCDC170 may promote apoptosis through the IRE1? pathway.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7835043 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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CCDC170 affects breast cancer apoptosis through IRE1 pathway.

Wang Qiong Q Zhao Yanrui Y Zheng Hong H Wang Qinghua Q Wang Wei W Liu Ben B Han Hongwei H Zhang Lina L Chen Kexin K

Aging 20201203 1

Genome-wide association studies have revealed that multiple single-nucleotide polymorphisms in the intergenic region between estrogen receptor 1 and coiled-coil domain containing 170 (<i>CCDC170</i>) are associated with breast cancer risk. We performed microarray and bioinformatics analyses to identify genes that were induced upon CCDC170 overexpression, and confirmed our findings by evaluating paraffin-embedded breast cancer tissues and conducting cellular assays. In CCDC170-overexpressing MCF7 ...[more]

PMID: 33291081

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Project description:BackgroundUbiquitin-conjugating enzyme E2C (UBE2C) has been shown to be associated with the occurrence of various cancers and involved in many tumorigenic processes. This study aimed to investigate the specific molecular mechanism through which UBE2C affects breast cancer (BC) proliferation.MethodsBC-related datasets were screened according to filter criteria in the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. Then differentially expressed genes (DEGs) were identified using Venn diagram analysis. By using DEGs, we conducted the following analyses including Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI), and survival analysis, and then validated the function of the hub gene UBE2C using quantitative reverse transcription-polymerase chain reaction (RT-qPCR), cell counting kit-8 (CCK-8) assay, transwell assay, and Western blot assay.ResultsIn total, 151 DEGs were identified from the GEO and TCGA databases. The results of GO analysis demonstrated that the DEGs were significantly enriched with mitotic nuclear division, lipid droplet, and organic acid-binding. KEGG analysis showed that the peroxisome proliferators-activated receptor (PPAR) signaling pathway, regulation of lipolysis in adipocytes, and proximal tubule bicarbonate reclamation were significantly enriched in the signal transduction pathway category. The top three hub genes that resulted from the PPI network were FOXM1, UBE2C, and CDKN3. The results of survival analysis showed a close relationship between UBE2C and BC. The results of CCK-8 and transwell assays suggested that the proliferation and invasion of UBE2C knockdown cells were significantly inhibited (P < 0.050). The results of Western blot assay showed that the level of phosphorylated phosphatase and tensin homology deleted on chromosome 10 (p-PTEN) was obviously increased (P < 0.050), whereas the levels of phosphorylated protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), and hypoxia-inducible factor-1 alpha (HIF-1α) were dramatically decreased (P < 0.050) in the UBE2C knockdown cell.ConclusionUBE2C can promote BC proliferation by activating the AKT/mTOR signaling pathway.

Project description:BACKGROUND:Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. METHODS:The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. RESULTS:Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. CONCLUSION:ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.

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CCDC170 affects breast cancer apoptosis through IRE1 pathway.

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CCDC170 affects breast cancer apoptosis through IRE1 pathway.

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