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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Association of tamoxifen resistance and lipid reprogramming in breast cancer

Authors: Susanne Hultsch, Matti Kankainen, Lassi Paavolainen, Ruusu-Maaria Kovanen, Elina Ikonen, Sara Kangaspeska, Vilja Pietiäinen, Olli Kallioniemi

Published in: BMC Cancer | Issue 1/2018

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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.
Appendix
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Metadata
Title
Association of tamoxifen resistance and lipid reprogramming in breast cancer
Authors
Susanne Hultsch
Matti Kankainen
Lassi Paavolainen
Ruusu-Maaria Kovanen
Elina Ikonen
Sara Kangaspeska
Vilja Pietiäinen
Olli Kallioniemi
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4757-z

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