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

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.

• Authors: Johanna M Buschhaus, Shrila Rajendran, Brock A Humphries, Alyssa C Cutter, Ayşe J Muñiz, Nicholas G Ciavattone, Alexander M Buschhaus, Tatiana Cañeque, Zeribe C Nwosu, Debashis Sahoo, Avinash S Bevoor, Yatrik M Shah, Costas A Lyssiotis, Pradipta Ghosh, Max S Wicha, Raphaël Rodriguez, Gary D Luker
• Journal: Oncogene (Oncogene) Vol. 41 Issue 29 Pg. 3705-3718 (07 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35732800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Estrogen Antagonists
• Estrogens
• Receptors, Estrogen
• Iron

Topics

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