Association of tamoxifen resistance and lipid reprogramming in breast cancer

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Hultsch , S , Kankainen , M , Paavolainen , L , Kovanen , R-M , Ikonen , E , Kangaspeska , S , Pietiäinen , V & Kallioniemi , O 2018 , ' Association of tamoxifen resistance and lipid reprogramming in breast cancer ' , BMC Cancer , vol. 18 , 850 .

Title: Association of tamoxifen resistance and lipid reprogramming in breast cancer
Author: Hultsch, Susanne; Kankainen, Matti; Paavolainen, Lassi; Kovanen, Ruusu-Maaria; Ikonen, Elina; Kangaspeska, Sara; Pietiäinen, Vilja; Kallioniemi, Olli
Contributor organization: Institute for Molecular Medicine Finland
University of Helsinki
Doctoral Programme in Biomedicine
Doctoral Programme in Integrative Life Science
Lipid Trafficking Lab
Department of Anatomy
Olli-Pekka Kallioniemi / Principal Investigator
Precision Systems Medicine
Date: 2018-08-24
Language: eng
Number of pages: 14
Belongs to series: BMC Cancer
ISSN: 1471-2407
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.
Subject: Tamoxifen resistance
Breast cancer
Lysosomal membrane permeabilization
Drug sensitivity and resistance testing
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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