The majority of breast tumours express oestrogen receptor (ER) and are dependent on oestrogen (E2) for their growth and survival. Endocrine therapy is the standard of care for this breast cancer subset and acts by targeting ER pathway in different ways: selective ER modulators compete with E2 to bind ER (e.g. tamoxifen), selective ER downregulators promote ER degradation (e.g. fulvestrant) and aromatase inhibitors (AI) block E2 biosynthesis. Despite the efficacy of these endocrine agents, a large proportion of women relapse with endocrine-resistant disease. In this study, we investigated the link between altered breast cancer metabolism and endocrine therapy resistance. We found that AI-resistance cells can adapt to metabolic stress and switch ad hoc between OXPHOS and glycolysis. In particular, we identified the miR-155/hexokinase-2 (HK2) axis as an important regulator of this tumour plasticity. In addition to central carbon metabolism, we found a deregulated node between miR-23b-3p and the amino acid transporter SLC6A14 in endocrine therapy resistant cells, which leads to an impairment of amino acids metabolism in the resistant cells with subsequent activation of autophagy. Furthermore, the miRNA characterised have prognostic (miR-155 and miR-23b-3p) and predictive (miR155) value in ER positive breast cancer. These results suggest that high metabolic plasticity is involved in acquiring adaptive features that allow breast cancer cell survival even in the presence of endocrine therapy
