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 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. Overall design: Co-culture model of bone marrow mesenchymal stem cells (MSCs) and ER+ breast cancer cells. Co-cultured cancer and stromal cells were separated before performing RNA sequencing. Data sets also include monoculture samples of cancer and stromal cells as well as cancer cells with conditioned medium from stromal cells.