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Association of tamoxifen resistance and lipid reprogramming in breast cancer

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 m...

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Autores principales: Hultsch, Susanne, Kankainen, Matti, Paavolainen, Lassi, Kovanen, Ruusu-Maaria, Ikonen, Elina, Kangaspeska, Sara, Pietiäinen, Vilja, Kallioniemi, Olli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109356/
https://www.ncbi.nlm.nih.gov/pubmed/30143015
http://dx.doi.org/10.1186/s12885-018-4757-z
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author Hultsch, Susanne
Kankainen, Matti
Paavolainen, Lassi
Kovanen, Ruusu-Maaria
Ikonen, Elina
Kangaspeska, Sara
Pietiäinen, Vilja
Kallioniemi, Olli
author_facet Hultsch, Susanne
Kankainen, Matti
Paavolainen, Lassi
Kovanen, Ruusu-Maaria
Ikonen, Elina
Kangaspeska, Sara
Pietiäinen, Vilja
Kallioniemi, Olli
author_sort Hultsch, Susanne
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-018-4757-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-61093562018-08-29 Association of tamoxifen resistance and lipid reprogramming in breast cancer Hultsch, Susanne Kankainen, Matti Paavolainen, Lassi Kovanen, Ruusu-Maaria Ikonen, Elina Kangaspeska, Sara Pietiäinen, Vilja Kallioniemi, Olli BMC Cancer Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-018-4757-z) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-24 /pmc/articles/PMC6109356/ /pubmed/30143015 http://dx.doi.org/10.1186/s12885-018-4757-z Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Hultsch, Susanne
Kankainen, Matti
Paavolainen, Lassi
Kovanen, Ruusu-Maaria
Ikonen, Elina
Kangaspeska, Sara
Pietiäinen, Vilja
Kallioniemi, Olli
Association of tamoxifen resistance and lipid reprogramming in breast cancer
title Association of tamoxifen resistance and lipid reprogramming in breast cancer
title_full Association of tamoxifen resistance and lipid reprogramming in breast cancer
title_fullStr Association of tamoxifen resistance and lipid reprogramming in breast cancer
title_full_unstemmed Association of tamoxifen resistance and lipid reprogramming in breast cancer
title_short Association of tamoxifen resistance and lipid reprogramming in breast cancer
title_sort association of tamoxifen resistance and lipid reprogramming in breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109356/
https://www.ncbi.nlm.nih.gov/pubmed/30143015
http://dx.doi.org/10.1186/s12885-018-4757-z
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