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Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer
- Buschhaus, Johanna M;
- Rajendran, Shrila;
- Humphries, Brock A;
- Cutter, Alyssa C;
- Muñiz, Ayşe J;
- Ciavattone, Nicholas G;
- Buschhaus, Alexander M;
- Cañeque, Tatiana;
- Nwosu, Zeribe C;
- Sahoo, Debashis;
- Bevoor, Avinash S;
- Shah, Yatrik M;
- Lyssiotis, Costas A;
- Ghosh, Pradipta;
- Wicha, Max S;
- Rodriguez, Raphaël;
- Luker, Gary D
- et al.
Published Web Location
https://doi.org/10.1038/s41388-022-02385-9Abstract
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.
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