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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Bone marrow mesenchymal stem cells combined with estrogen synergistically promote endometrial regeneration and reverse EMT via Wnt/β-catenin signaling pathway
Reproductive Biology and Endocrinology Open Access 15 August 2022
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We thank Sean Linkes, Ann Marie Deslauriers-Cox, and Michael Pihalja for assistance with Flow cytometry. We acknowledge support from the Advanced Genomics Core, the Flow Cytometry Core, and the Center for Molecular Imaging Core of the University of Michigan Medical School’s Biomedical Research Core Facilities.
We acknowledge support to the University of Michigan Rogel Cancer Center through National Institutes of Health grant P30CA046592 for flow cytometry and animal imaging studies. The authors acknowledge funding from NIH grants R01CA100768, R01CA238042, R01GM138385, R01CA148828, R01CA245546, R01DK095201, R01CA248160, R35CA197585, R01CA2449310, U01CA210152, R01CA238023, R33CA225549, R50CA221807, and R37CA222563 and funding from the Breast Cancer Research Foundation grant BCRF-18-173. RR lab is funded by the European Research Council under the European Union’s Horizon 2020 research and innovation programme grant agreement No 647973 (R.R.), the Foundation Charles Defforey-Institut de France, and Ligue Contre le Cancer Equipe Labellisée. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE 1256260 (JMB and AJM). BAH, Ph.D., was supported by an American Cancer Society - Michigan Cancer Research Fund Postdoctoral Fellowship, PF-18-236-01-CCG. ZCN is supported by the Michigan Postdoctoral Pioneer Program at the University of Michigan Medical School.
CAL has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapuetics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). GDL has received research funding from InterAx Biotech AG and Polyphor (now part of Spexis). The remaining authors declare no competing interests.
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Buschhaus, J.M., Rajendran, S., Humphries, B.A. et al. Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer. Oncogene 41, 3705–3718 (2022). https://doi.org/10.1038/s41388-022-02385-9
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