Chemotherapy Triggers HIF-1-dependent Glutathione Synthesis and Copper Chelation That Induces the Breast Cancer Stem Cell Phenotype

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Aug 1

PMID 26229077

Citations 136

Authors

Haiquan Lu

Debangshu Samanta

Lisha Xiang

Huimin Zhang

Hongxia Hu

Ivan Chen

John W Bullen

Gregg L Semenza

Affiliations

Soon will be listed here.

Abstract

Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.

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