Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment

Haiquan Lu, Ivan Chen, Larissa Shimoda, Youngrok Park, Chuanzhao Zhang, Linh Tran, Huimin Zhang, Gregg L Semenza

Research output: Contribution to journalArticle

Abstract

Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with the ryanodine receptor RYR1 and promotes calcium release from the endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer.

Original languageEnglish (US)
Pages (from-to)1946-1957
Number of pages12
JournalCell Reports
Volume18
Issue number8
DOIs
StatePublished - Feb 21 2017

Keywords

  • breast cancer stem cell
  • chemotherapy
  • hypoxia-inducible factors
  • metastasis
  • pluripotency factors
  • tumor initiation
  • tumor recurrence

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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