Paracrine Crosstalk between Fibroblasts and ER⁺ Breast Cancer Cells Creates an IL1β-Enriched Niche that Promotes...

Breast cancer-induced activated fibroblasts support tumor progression. However, the role of normal fibroblasts in tumor progression remains controversial. In this study, we used modified patient-derived organoid cultures and demonstrate that constitutively secreted cytokines from normal breast fibroblasts initiate a paracrine signaling mechanism with estrogen receptor-positive (ER⁺) breast cancer cells, which results in the creation of an interleukin (IL)-1β-enriched microenvironment. We found that this paracrine signaling mechanism is shared between normal and activated fibroblasts. Interestingly, we observed that in reconstructed tumor microenvironment containing autologous ER⁺ breast cancer cells, activated fibroblasts, and immune cells, tamoxifen is more effective in reducing tumor cell proliferation when this paracrine signaling is blocked. Our findings then suggest that ER⁺ tumor cells could create a growth-promoting environment without activating stromal fibroblasts and that in breast-conserving surgeries, normal fibroblasts could be a significant modulator of tumor recurrence by enhancing the proliferation of residual breast cancer cells in the tumor-adjacent breast tissue.