Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen

Purpose: Antiendocrine therapy remains the most effective treatment for estrogen receptor-positive (ER⁺) breast cancer, but development of resistance is a major clinical complication. Effective targeting of mechanisms that control the loss of ER dependency in breast cancer remains elusive. We analyzed breast cancer-associated fibroblasts (CAF), the largest component of the tumor microenvironment, as a factor contributing to ER expression levels and antiendocrine resistance. Experimental Design: Tissues from patients with ER⁺ breast cancer were analyzed for the presence of CD146-positive (CD146^pos) and CD146-negative (CD146^neg) fibroblasts. ER-dependent proliferation and tamoxifen sensitivity were evaluated in ER⁺ tumor cells cocultured with CD146^pos or CD146^neg fibroblasts. RNA sequencing was used to develop a highconfidence gene signature that predicts for disease recurrence in tamoxifen-treated patients with ER⁺ breast cancer. Results: We demonstrate that ER⁺ breast cancers contain two CAF subtypes defined by CD146 expression. CD146^neg CAFs suppress ER expression in ER⁺ breast cancer cells, decrease tumor cell sensitivity to estrogen, and increase tumor cell resistance to tamoxifen therapy. Conversely, the presence of CD146^pos CAFs maintains ER expression in ER⁺ breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146^pos CAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146^neg CAFs correlate with inferior clinical response to tamoxifen and worse patient outcomes. Conclusions: Our data suggest that CAF composition contributes to treatment response and patient outcomes in ER⁺ breast cancer and should be considered a target for drug development.