PMID- 37378696
OWN - NLM
STAT- MEDLINE
DCOM- 20230724
LR  - 20230724
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 201
IP  - 2
DP  - 2023 Sep
TI  - HSD17B4 methylation enhances glucose dependence of BT-474 breast cancer cells and 
      increases lapatinib sensitivity.
PG  - 317-328
LID - 10.1007/s10549-023-07013-y [doi]
AB  - PURPOSE: HER2-positive breast cancer has a high chance of achieving pathological 
      complete response when HSD17B4, responsible for peroxisomal beta-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.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business 
      Media, LLC, part of Springer Nature.
FAU - Arai, Nobuaki
AU  - Arai N
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
AD  - Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan.
FAU - Hattori, Naoko
AU  - Hattori N
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
AD  - Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi 
      University, Tokyo, Japan.
FAU - Yamashita, Satoshi
AU  - Yamashita S
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
FAU - Liu, Yu-Yu
AU  - Liu YY
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
AD  - Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi 
      University, Tokyo, Japan.
FAU - Ebata, Takahiro
AU  - Ebata T
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
AD  - Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi 
      University, Tokyo, Japan.
FAU - Takeuchi, Chihiro
AU  - Takeuchi C
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
AD  - Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi 
      University, Tokyo, Japan.
FAU - Takeshima, Hideyuki
AU  - Takeshima H
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
AD  - Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi 
      University, Tokyo, Japan.
FAU - Fujii, Satoshi
AU  - Fujii S
AD  - Department of Molecular Pathology, Yokohama City University Graduate School of 
      Medicine, Kanagawa, Japan.
FAU - Kondo, Haruhiko
AU  - Kondo H
AD  - Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan.
FAU - Mukai, Hirofumi
AU  - Mukai H
AD  - Department of Medical Oncology, National Cancer Center Hospital East, Chiba, 
      Japan.
FAU - Ushijima, Toshikazu
AU  - Ushijima T
AUID- ORCID: 0000-0003-3405-7817
AD  - Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. 
      tushijima142@hoshi.ac.jp.
AD  - Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi 
      University, Tokyo, Japan. tushijima142@hoshi.ac.jp.
LA  - eng
GR  - JP19ck0106466/Japan Agency for Medical Research and Development/
GR  - JP23ck0106832/Japan Agency for Medical Research and Development/
PT  - Journal Article
DEP - 20230628
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0VUA21238F (Lapatinib)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - IY9XDZ35W2 (Glucose)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 4.2.1.119 (HSD17B4 protein, human)
RN  - EC 4.2.1.107 (Peroxisomal Multifunctional Protein-2)
SB  - IM
MH  - Humans
MH  - Female
MH  - Lapatinib/pharmacology
MH  - *Breast Neoplasms/drug therapy/genetics/metabolism
MH  - Methylation
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Glucose
MH  - Cell Line, Tumor
MH  - Receptor, ErbB-2/genetics/metabolism
MH  - Peroxisomal Multifunctional Protein-2/genetics/metabolism
OTO - NOTNLM
OT  - DNA methylation
OT  - Epigenetics
OT  - HER2-positive breast cancer
OT  - Metabolic vulnerability
OT  - Neoadjuvant chemotherapy
EDAT- 2023/06/28 13:08
MHDA- 2023/07/24 06:42
CRDT- 2023/06/28 11:04
PHST- 2023/04/07 00:00 [received]
PHST- 2023/06/16 00:00 [accepted]
PHST- 2023/07/24 06:42 [medline]
PHST- 2023/06/28 13:08 [pubmed]
PHST- 2023/06/28 11:04 [entrez]
AID - 10.1007/s10549-023-07013-y [pii]
AID - 10.1007/s10549-023-07013-y [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2023 Sep;201(2):317-328. doi: 
      10.1007/s10549-023-07013-y. Epub 2023 Jun 28.