Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer

Oncogene. 2022 Jul;41(29):3705-3718. doi: 10.1038/s41388-022-02385-9. Epub 2022 Jun 22.

Abstract

Patients with estrogen receptor-positive (ER+) breast cancer, the most common subtype, remain at risk for lethal metastatic disease years after diagnosis. Recurrence arises partly because tumor cells in bone marrow become resistant to estrogen-targeted therapy. Here, we utilized a co-culture model of bone marrow mesenchymal stem cells (MSCs) and ER+ breast cancer cells to recapitulate interactions of cancer cells in bone marrow niches. ER+ breast cancer cells in direct contact with MSCs acquire cancer stem-like (CSC) phenotypes with increased resistance to standard antiestrogenic drugs. We confirmed that co-culture with MSCs increased labile iron in breast cancer cells, a phenotype associated with CSCs and disease progression. Clinically approved iron chelators and in-house lysosomal iron-targeting compounds restored sensitivity to antiestrogenic therapy. These findings establish iron modulation as a mechanism to reverse MSC-induced drug resistance and suggest iron modulation in combination with estrogen-targeted therapy as a promising, translatable strategy to treat ER+ breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Drug Resistance
  • Drug Resistance, Neoplasm
  • Estrogen Antagonists / pharmacology
  • Estrogens / pharmacology
  • Iron
  • Mesenchymal Stem Cells*
  • Neoplasms*
  • Receptors, Estrogen

Substances

  • Estrogen Antagonists
  • Estrogens
  • Receptors, Estrogen
  • Iron