Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer

Ji Young Kim, Youngkwan Cho, Eunhye Oh, Nahyun Lee, Hyunsook An, Daeil Sung, Tae Min Cho, Jae Hong Seo

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

HER2-positive breast tumors are known to harbor cancer stem-like cell populations and are associated with an aggressive tumor phenotype and poor clinical outcomes. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in many cancer cell types in the presence of copper (Cu). The objective of the present study was to investigate the mechanism of action responsible for the induction of apoptosis by DSF/Cu and its effect on cancer stem cell properties in HER2-positive breast cancers in vitro and in vivo.DSF/Cu treatment induced apoptosis, associated with a marked decrease in HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels, and p27 nuclear accumulation. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere formation. DSF administration resulted in a significant reduction in tumor growth and an enhancement of apoptosis, as well as HER2 intracellular domain (ICD) and ALDH1A1 downregulation. Our results demonstrate that DSF/Cu induces apoptosis and eliminates cancer stem-like cells via the suppression of HER2/Akt signaling, suggesting that DSF may be potentially effective for the treatment of HER2-positive cancers.

Original languageEnglish
Pages (from-to)39-48
Number of pages10
JournalCancer Letters
Volume379
Issue number1
DOIs
Publication statusPublished - 2016 Aug 28

Fingerprint

Disulfiram
Breast Neoplasms
Neoplastic Stem Cells
Apoptosis
Tumors
Neoplasms
Cells
Cytotoxicity
Ports and harbors
Stem cells
Population
Alcoholism
Copper
Down-Regulation
Phenotype
Growth
Pharmaceutical Preparations

Keywords

  • ALDH1A1
  • Apoptosis
  • Disulfiram
  • HER2
  • P95HER2
  • Trastuzumab resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer. / Kim, Ji Young; Cho, Youngkwan; Oh, Eunhye; Lee, Nahyun; An, Hyunsook; Sung, Daeil; Cho, Tae Min; Seo, Jae Hong.

In: Cancer Letters, Vol. 379, No. 1, 28.08.2016, p. 39-48.

Research output: Contribution to journalArticle

Kim, Ji Young ; Cho, Youngkwan ; Oh, Eunhye ; Lee, Nahyun ; An, Hyunsook ; Sung, Daeil ; Cho, Tae Min ; Seo, Jae Hong. / Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer. In: Cancer Letters. 2016 ; Vol. 379, No. 1. pp. 39-48.
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