Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis

Obesity is predicted to become the largest modifiable risk factor for breast cancer in postmenopausal women, yet the mechanisms underlying this association are unclear. We identified a novel protective mechanism for lean adipocytes to suppress breast cancer by secreting the oxylipin 9S-HODE, which induces ferroptosis in breast cancer cells while sparing normal breast epithelial cells. Consequently, the inhibition of ferroptosis accelerates breast cancer in lean, but not obese, mice. Obese adipocytes fail to secrete 9S-HODE, suggesting that the loss of 9S-HODE significantly contributes to the acceleration of breast cancer in obesity. Further, 9S-HODE supplementation into tumors in obese mice is sufficient to reduce tumor burden and additionally can inhibit the growth of patient-derived breast cancer organoids, underscoring its potential as a therapeutic agent. Overall design: RNA-sequencing profile of E0771, SkBr3 and NMuMG breast cancer cells were treated with control DMEM Obese inguinal adipocyte secretome or lean inguinal adipocyte secretome.