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

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 o...

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Bibliographic Details
Published in:	Oncogene Vol. 41; no. 29; pp. 3705 - 3718
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 15-07-2022 Nature Publishing Group Nature Publishing Group [1987-....]
Subjects:	13/106 13/109 13/31 14/34 14/35 14/5 38/91 59/5 631/67/1347 631/67/71 631/80/304 64/60 Apoptosis Bone cancer Bone marrow Bone tumors Breast cancer Cell Biology Cell culture Cell Line, Tumor Chelating agents Chemical Sciences Drug Resistance Drug Resistance, Neoplasm Estrogen Antagonists - pharmacology Estrogen receptors Estrogens Estrogens - pharmacology Human Genetics Internal Medicine Iron Life Sciences Medicine Medicine & Public Health Mesenchymal Stem Cells Metastases Neoplasms Oncology Phenotypes Receptors, Estrogen Stem cells Tumor cells
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC9288981 JMB conceptualized and designed the study, performed experiments, wrote MATLAB code, acquired funding, analyzed data, performed bioinformatics analyses, and wrote the paper. SR performed experiments, analyzed data, and wrote the paper. BAH provided reagents, performed experiments, acquired funding, and analyzed data. ACC, NGC, AMB, and ASB performed experiments. AJM performed experiments and acquired funding. TC provided reagents. YMS, MSW, and RR provided reagents and acquired funding. ZCN, DS, and PG acquired funding and performed bioinformatics analyses. CAL provided reagents, acquired funding, and performed bioinformatics analyses. GDL conceptualized and designed the study, acquired funding, and wrote the paper. All authors reviewed the paper before submission. Author Contributions
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-022-02385-9