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

Cell Rep. 2017 Feb 21;18(8):1946-1957. doi: 10.1016/j.celrep.2017.02.001.


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.

Keywords: breast cancer stem cell; chemotherapy; hypoxia-inducible factors; metastasis; pluripotency factors; tumor initiation; tumor recurrence.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Calcium / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / metabolism
  • Cytosol / metabolism
  • Female
  • Glutathione Transferase / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • MCF-7 Cells
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / physiology
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects


  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ryanodine Receptor Calcium Release Channel
  • STAT3 Transcription Factor
  • endothelial PAS domain-containing protein 1
  • GSTO1 protein, human
  • Glutathione Transferase
  • Calcium