NRG1/PDGFC loop between fibroblasts and cancer cells drives paclitaxel resistance via ferroptosis suppression in breast cancer.

Breast cancer (BC) is one of the leading diseases that severely threaten women's lives and health worldwide, with chemoresistance remaining a major challenge in its treatment. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a critical role in the chemoresistance of tumor cells, but the underlying mechanisms involved still require further exploration. This study aims to investigate the role and potential mechanisms of the positive feedback loop formed by CAF-derived NRG1 and BC cell-derived PDGFC in paclitaxel resistance. To this end, we isolated primary CAFs from BC patients and established co-culture systems with BC cell lines to observe the impact of CAFs on paclitaxel resistance in BC cells. Exogenous NRG1 and the knockdown of NRG1 in CAFs were used to reveal the regulatory role of CAF-derived NRG1 in paclitaxel resistance in BC cells. CCK-8 assay, transmission electron microscopy, MDA and GSH/GSSG content measurements, as well as JC-1 assay, were used to assess ferroptosis levels in BC cells. Additionally, exogenous PDGFC and co-culture systems were used to investigate the effects of tumor cell-derived PDGFC on fibroblasts. Using a BC ectopic xenograft mouse model, we investigated the regulatory role of NRG1 and PDGFC in paclitaxel resistance in vivo. Our results showed that CAF-derived NRG1 significantly promoted paclitaxel resistance and ferroptosis escape in BC cells, while the AKT inhibitor effectively suppressed this effect. Moreover, BC cell-derived PDGFC activated fibroblasts and induced their high expression of NRG1. These findings suggest that CAF-derived NRG1 enhances ferroptosis escape and paclitaxel resistance in BC cells through the AKT/mTOR pathway, while also inducing cancer cells to express high levels of PDGFC. In turn, cancer cell-derived PDGFC promotes fibroblast activation and high NRG1 expression, forming a positive feedback loop between NRG1 and PDGFC. This feedback loop ultimately results in a malignant cycle of paclitaxel resistance in BC.