HSD17B4 methylation enhances glucose dependence of BT-474 breast cancer cells and increases lapatinib sensitivity.

Abstract

PURPOSE:

HER2-positive breast cancer has a high chance of achieving pathological complete response when HSD17B4, responsible for peroxisomal β-oxidation of very long-chain fatty acids (VLCFA) and estradiol, is methylation-silenced. Here, we aimed to identify the underlying molecular mechanism.

METHODS:

Using a HER2-positive breast cancer cell line, BT-474, control and knock-out (KO) clones were obtained. Metabolic characteristics were analyzed using a Seahorse Flux analyzer.

RESULTS:

HSD17B4 KO suppressed cellular proliferation, and enhanced sensitivity to lapatinib approximately tenfold. The KO led to accumulation of VLCFA and a decrease of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid. HSD17B4 KO increased Akt phosphorylation, possibly via decreased DHA, and genes involved in oxidative phosphorylation (OxPhos) and electron transport chain (ETC) were upregulated. Increased mitochondrial ATP production in the KO cells was confirmed by extracellular flux analyzer. Increased OxPhos led to severe dependence of the KO cells on pyruvate from glycolysis. Suppression of glycolysis by lapatinib led to severe delayed suppression of OxPhos in KO cells.

CONCLUSION:

HSD17B4 KO in BT-474 cells caused a decrease of PUFAs, increased Akt phosphorylation, enhanced glucose dependence of OxPhos, and increased sensitivity to inhibition of HER2, upstream of Akt. This mechanism may be applicable to other HER2-positive glucose-dependent breast cancer cells with HSD17B4 silencing.

• Authors: Nobuaki Arai, Naoko Hattori, Satoshi Yamashita, Yu-Yu Liu, Takahiro Ebata, Chihiro Takeuchi, Hideyuki Takeshima, Satoshi Fujii, Haruhiko Kondo, Hirofumi Mukai, Toshikazu Ushijima
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 201 Issue 2 Pg. 317-328 (Sep 2023) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 37378696 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Lapatinib
• Proto-Oncogene Proteins c-akt
• Glucose
• Receptor, ErbB-2
• HSD17B4 protein, human
• Peroxisomal Multifunctional Protein-2

Topics

• Humans
• Female
• Lapatinib (pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Methylation
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Glucose
• Cell Line, Tumor
• Receptor, ErbB-2 (genetics, metabolism)
• Peroxisomal Multifunctional Protein-2 (genetics, metabolism)