One-third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need.  Here we identify a specific post-translational modification that occurs during endocrine resistance and which results in tumour susceptibility to the apoptosis inducer TNF-Related Apoptosis-Inducing Ligand (TRAIL). This potentially offers a novel stratified approach to targeting endocrine resistant breast cancer.