Dataset Information

Identification and Analysis of Estrogen Receptor ? Promoting Tamoxifen Resistance-Related lncRNAs.

ABSTRACT: 70-75% breast cancer patients are estrogen receptor alpha positive (ER?+), and the antiestrogen drug tamoxifen has been used for the past three decades. However, in 20-30% of these patients, tamoxifen therapy fails due to intrinsic or acquired resistance. A previous study has showed ER? signaling still exerts significant roles in the development of tamoxifen resistance and several lncRNAs have been demonstrated important roles in tamoxifen resistance. But ER? directly regulated and tamoxifen resistance related lncRNAs remain to be discovered. We reanalyze the published ER? chromatin immunoprecipitation-seq (ChIP-seq) and RNA-seq data of tamoxifen-sensitive (MCF-7/WT) and tamoxifen-resistant (MCF-7/TamR) breast cancer cells. We demonstrate that there are differential ER? recruitment events and the differentials may alert the expression profile in MCF-7/WT and MCF-7/TamR cells. Furthermore, we make an overlap of the ER? binding lncRNAs and differentially expressed lncRNAs and get 49 ER? positively regulated lncRNAs. Among these lncRNAs, the expression levels of AC117383.1, AC144450.1, RP11-15H20.6, and ATXN1-AS1 are negatively correlated with the survival probability of breast cancer patients and ELOVL2-AS1, PCOLCE-AS1, ITGA9-AS1, and FLNB-AS1 are positively correlated. These lncRNAs may be potential diagnosis or prognosis markers of tamoxifen resistance.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7204353 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Identification and Analysis of Estrogen Receptor α Promoting Tamoxifen Resistance-Related lncRNAs.

Zhang Xiulei X Gao Shanjun S Li Zhen Z Wang Wei W Liu Guangzhi G

BioMed research international 20200428

70-75% breast cancer patients are estrogen receptor alpha positive (ERα+), and the antiestrogen drug tamoxifen has been used for the past three decades. However, in 20-30% of these patients, tamoxifen therapy fails due to intrinsic or acquired resistance. A previous study has showed ERα signaling still exerts significant roles in the development of tamoxifen resistance and several lncRNAs have been demonstrated important roles in tamoxifen resistance. But ERα directly regula ...[more]

PMID: 32420379

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Project description:Estrogen receptor (ER) ? is a successful therapeutic target in breast cancer, but patients eventually develop resistance to antiestrogens such as tamoxifen.To identify genes whose expression was associated with the development of tamoxifen resistance and metastasis, we used microarrays to compare gene expression in four primary tumors from tamoxifen-treated patients whose breast cancers did not recur vs five metastatic tumors from patients whose cancers progressed during adjuvant tamoxifen treatment. Because Rho guanine dissociation inhibitor (GDI) ? was underexpressed in the tamoxifen-resistant group, we stably transfected ER?-positive MCF-7 breast cancer cells with a plasmid encoding a short hairpin (sh) RNA to silence Rho GDI? expression. We used immunoblots and transcription assays to examine the role of Rho GDI? in ER-related signaling and growth of cells in vitro and as xenografts in treated nude mice (n = 8-9 per group) to examine the effects of Rho GDI? blockade on hormone responsiveness and metastatic behavior. The time to tumor tripling as the time in weeks from randomization to a threefold increase in total tumor volume over baseline was examined in treated mice. The associations of Rho GDI? and MTA2 levels with tamoxifen resistance were examined in microarray data from patients. All statistical tests were two-sided.Rho GDI? was expressed at lower levels in ER?-positive tumors that recurred during tamoxifen treatment than in ER?-positive tamoxifen-sensitive primary tumors. MCF-7 breast cancer cells in which Rho GDI? expression had been silenced were tamoxifen-resistant, had increased Rho GTPase and p21-activated kinase 1 activity, increased phosphorylation of ER? at serine 305, and enhanced tamoxifen-induced ER? transcriptional activity compared with control cells. MCF-7 cells in which Rho GDI? expression was silenced metastasized with high frequency when grown as tumor xenografts. When mice were treated with estrogen or estrogen withdrawal, tripling times for xenografts from cells with Rho GDI? silencing were similar to those from vector-containing control cells; however, tripling times were statistically significantly faster than control when mice were treated with tamoxifen (median tripling time for tumors with Rho GDI? small interfering RNA = 2.34 weeks; for control tumors = not reached, hazard ratio = 4.13, 95% confidence interval = 1.07 to 15.96, P = .040 [adjusted for multiple comparisons, P = .119]). Levels of the metastasis-associated protein MTA2 were also increased upon Rho GDI? silencing, and combined Rho GDI? and MTA2 levels were associated with recurrence in 250 tamoxifen-treated patients.Loss of Rho GDI? enhances metastasis and resistance to tamoxifen via effects on both ER? and MTA2 in models of ER?-positive breast cancer and in tumors of tamoxifen-treated patients.

Dataset Information

Identification and Analysis of Estrogen Receptor ? Promoting Tamoxifen Resistance-Related lncRNAs.

Publications

Identification and Analysis of Estrogen Receptor <i>α</i> Promoting Tamoxifen Resistance-Related lncRNAs.

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