Estrogen receptor-positive (ER+) breast cancer kills more women than any other breast cancer subtype. Despite the good 5-year prognosis and initial response to adjuvant endocrine therapy, many women eventually develop local and distant recurrent disease. Endocrine-resistant disease is refractory to both endocrine and chemotherapeutic strategies, limiting treatment options. The development of biomarkers to predict long-term response to endocrine therapy in these patients and the molecular mechanisms of resistance represent a current clinical need. The recent development of immune therapies has opened an array of new treatment potential for cancer.
We have identified the transcription factor ELF5 as a key determinant of anti-estrogen resistance1 and metastatic spread2 in luminal breast cancer. High ELF5 expression in ER+ luminal A patients predicts an 11-fold higher risk of dying in the first 5 years; and inversely correlates with infiltrated T-CD8 cytotoxic lymphocytes, indicating immune tolerance2. Using the PyMT mouse model of luminal breast cancer we demonstrated the pro-metastatic effect of ELF5 and its role co-opting the immune system and promoting T-CD8 immune tolerance through the recruitment myeloid-derived suppressor cells (MDSC) to the tumour2. Importantly, in this model, depletion of MDSC results in a significant reduction of the metastatic burden2, providing proof-of-concept for the use of targeted immunotherapy for luminal breast cancer.
ELF5 has emerged as a key determinant of the progression towards the lethal phenotype in luminal breast cancer. We propose the use of ELF5 as a biomarker to identify luminal breast cancer patients that will benefit from a targeted adjuvant immunotherapy combined with the current first line of anti-estrogen therapy.