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Inverse agonist of estrogen-related receptor ? suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways.

ABSTRACT: There is an urgent clinical need for targeted therapy approaches for triple-negative breast cancer (TNBC) patients. Increasing evidences suggested that the expression of estrogen-related receptor alpha (ERR?) was correlate with unfavorable clinical outcomes of breast cancer patients. We here show that inhibition of ERR? by its inverse agonist XCT-790 can suppress the proliferation, decrease G2/M phases, and induce mitochondrial-related apoptosis of TNBC cells. XCT-790 elevates the proteins related to endoplasmic reticulum (ER) stress such as ATF4/6, XBT-1 and CHOP. It also increases the expression of growth inhibition related proteins such as p53 and p21. Further, XCT-790 can increase the generation of reactive oxygen species (ROS) in TNBC cells mainly through inhibition of SOD1/2. While ROS scavenger NAC abolishes XCT-790 induced ER-stress and growth arrest. XCT-790 treatment can rapidly activate the signal molecules including ERK1/2, p38-MAPK, JNK, Akt, p65, and I?B?, while NAC attenuates effects of XCT-790 induced phosphorylation of ERK1/2, p38-MAPK and Akt. Further, the inhibitors of ERK1/2, JNK, Akt, and NF-?B attenuate XCT-790 induced ROS generation. These data suggest that AKT/ROS and ERK/ROS positive feedback loops, NF-?B/ROS, and ROS/p38-MAPK, are activated in XCT-790 treated TNBC cells. In vivo experiments show that XCT-790 significantly suppresses the growth of MDA-MB-231 xenograft tumors, which is associated with up regulation of p53, p21, ER-stress related proteins while down regulation of bcl-2. The present discovery makes XCT-790 a promising candidate drug and lays the foundation for future development of ERR?-based therapies for TNBC patients.

SUBMITTER: Wu YM

PROVIDER: S-EPMC4914305 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways.

Wu Ying-Min YM Chen Zhuo-Jia ZJ Jiang Guan-Min GM Zhang Kun-Shui KS Liu Qiao Q Liang Shu-Wei SW Zhou Yan Y Huang Hong-Bin HB Du Jun J Wang Hong-Sheng HS

Oncotarget 20160301 11

There is an urgent clinical need for targeted therapy approaches for triple-negative breast cancer (TNBC) patients. Increasing evidences suggested that the expression of estrogen-related receptor alpha (ERRα) was correlate with unfavorable clinical outcomes of breast cancer patients. We here show that inhibition of ERRα by its inverse agonist XCT-790 can suppress the proliferation, decrease G2/M phases, and induce mitochondrial-related apoptosis of TNBC cells. XCT-790 elevates the proteins relat ...[more]

PMID: 26871469

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Project description:The recent surge of next generation sequencing of breast cancer genomes has enabled development of comprehensive catalogues of somatic mutations and expanded the molecular classification of subtypes of breast cancer. However, somatic mutations and gene expression data have not been leveraged and integrated with epigenomic data to unravel the genomic-epigenomic interaction landscape of triple negative breast cancer (TNBC) and non-triple negative breast cancer (non-TNBC). We performed integrative data analysis combining somatic mutation, epigenomic and gene expression data from The Cancer Genome Atlas (TCGA) to unravel the possible oncogenic interactions between genomic and epigenomic variation in TNBC and non-TNBC. We hypothesized that within breast cancers, there are differences in somatic mutation, DNA methylation and gene expression signatures between TNBC and non-TNBC. We further hypothesized that genomic and epigenomic alterations affect gene regulatory networks and signaling pathways driving the two types of breast cancer. The investigation revealed somatic mutated, epigenomic and gene expression signatures unique to TNBC and non-TNBC and signatures distinguishing the two types of breast cancer. In addition, the investigation revealed molecular networks and signaling pathways enriched for somatic mutations and epigenomic changes unique to each type of breast cancer. The most significant pathways for TNBC were: retinal biosynthesis, BAG2, LXR/RXR, EIF2 and P2Y purigenic receptor signaling pathways. The most significant pathways for non-TNBC were: UVB-induced MAPK, PCP, Apelin endothelial, Endoplasmatic reticulum stress and mechanisms of viral exit from host signaling Pathways. The investigation revealed integrated genomic, epigenomic and gene expression signatures and signing pathways unique to TNBC and non-TNBC, and a gene signature distinguishing the two types of breast cancer. The study demonstrates that integrative analysis of multi-omics data is a powerful approach for unravelling the genomic-epigenomic interaction landscape in TNBC and non-TNBC.

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Inverse agonist of estrogen-related receptor ? suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways.

Publications

Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways.

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