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Association of tamoxifen resistance and lipid reprogramming in breast cancer.

ABSTRACT: BACKGROUND:Tamoxifen treatment of estrogen receptor (ER)-positive breast cancer reduces mortality by 31%. However, over half of advanced ER-positive breast cancers are intrinsically resistant to tamoxifen and about 40% will acquire the resistance during the treatment. METHODS:In order to explore mechanisms underlying endocrine therapy resistance in breast cancer and to identify new therapeutic opportunities, we created tamoxifen-resistant breast cancer cell lines that represent the luminal A or the luminal B. Gene expression patterns revealed by RNA-sequencing in seven tamoxifen-resistant variants were compared with their isogenic parental cells. We further examined those transcriptomic alterations in a publicly available patient cohort. RESULTS:We show that tamoxifen resistance cannot simply be explained by altered expression of individual genes, common mechanism across all resistant variants, or the appearance of new fusion genes. Instead, the resistant cell lines shared altered gene expression patterns associated with cell cycle, protein modification and metabolism, especially with the cholesterol pathway. In the tamoxifen-resistant T-47D cell variants we observed a striking increase of neutral lipids in lipid droplets as well as an accumulation of free cholesterol in the lysosomes. Tamoxifen-resistant cells were also less prone to lysosomal membrane permeabilization (LMP) and not vulnerable to compounds targeting the lipid metabolism. However, the cells were sensitive to disulfiram, LCS-1, and dasatinib. CONCLUSION:Altogether, our findings highlight a major role of LMP prevention in tamoxifen resistance, and suggest novel drug vulnerabilities associated with this phenotype.

SUBMITTER: Hultsch S

PROVIDER: S-EPMC6109356 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Association of tamoxifen resistance and lipid reprogramming in breast cancer.

Hultsch Susanne S Kankainen Matti M Paavolainen Lassi L Kovanen Ruusu-Maaria RM Ikonen Elina E Kangaspeska Sara S Pietiäinen Vilja V Kallioniemi Olli O

BMC cancer 20180824 1

<h4>Background</h4>Tamoxifen treatment of estrogen receptor (ER)-positive breast cancer reduces mortality by 31%. However, over half of advanced ER-positive breast cancers are intrinsically resistant to tamoxifen and about 40% will acquire the resistance during the treatment.<h4>Methods</h4>In order to explore mechanisms underlying endocrine therapy resistance in breast cancer and to identify new therapeutic opportunities, we created tamoxifen-resistant breast cancer cell lines that represent th ...[more]

PMID: 30143015

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Project description:Background: Tamoxifen (TMX) is one of the most widely used drugs to treat breast cancer (BC). However, acquired drug resistance is still a major obstacle to its application, rendering it crucial to explore the mechanisms of TMX resistance in BC. This aims of this study were to identify the mechanisms of TMX resistance and construct ceRNA regulatory networks in breast cancer. Methods: GEO2R was used to screen for differentially expressed mRNAs (DEmRNAs) leading to drug resistance in BC cells. MiRTarbase and miRNet were used to predict miRNAs and lncRNAs upstream, and the competing endogenous RNA (ceRNA) regulatory network of BC cell resistance was constructed by starBase. We used the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) to analyze the expression and prognostic differences of genes in the ceRNA network with core axis, and qRT-PCR was used to further verify the above conclusions. Results: We found that 21 DEmRNAs were upregulated and 43 DEmRNA downregulated in drug-resistant BC cells. DEmRNAs were noticeably enriched in pathways relevant to cancer. We then constructed a protein-protein interaction (PPI) network based on the STRING database and defined 10 top-ranked hub genes among the upregulated and downregulated DEmRNAs. The 20 DEmRNAs were predicted to obtain 113 upstream miRNAs and 501 lncRNAs. Among them, 7 mRNAs, 22 lncRNAs, and 11 miRNAs were used to structure the ceRNA regulatory network of drug resistance in BC cells. 4 mRNAs, 4 lncRNAs, and 3 miRNAs were detected by GEPIA and the Kaplan-Meier plotter to be significantly associated with BC expression and prognosis. The differential expression of the genes in BC cells was confirmed by qRT-PCR. Conclusion: The ceRNA regulatory network of TMX-resistant BC was successfully constructed and confirmed. This will provide an important resource for finding therapeutic targets for TMX resistance, where the discovery of candidate conventional mechanisms can aid clinical decision-making. In addition, this resource will help discover the mechanisms behind this type of resistance.

Dataset Information

Association of tamoxifen resistance and lipid reprogramming in breast cancer.

Publications

Association of tamoxifen resistance and lipid reprogramming in breast cancer.

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