Biological determinants of endocrine resistance in breast cancer

Key Points Endocrine therapies that target oestrogen action (anti-oestrogens and aromatase inhibitors) are widely used and successful breast cancer therapies, but many women treated with these therapies will relapse with endocrine-resistant disease. Mechanisms of endocrine resistance in oestrogen receptor (ER)-positive breast cancers include loss of ERα expression and expression of truncated isoforms of ERα and ERβ, post-translational modifications of ERα, increased AP1 activity and deregulation of ER co-activators, increased receptor tyrosine kinase signalling leading to the activation of the Erk and PI3K pathways, and deregulation of the cell cycle and apoptotic machinery. Gene expression signatures that are predictive of poor outcome in women treated with tamoxifen commonly contain ER target genes, as well as genes involved in proliferation, apoptosis, and invasion and metastasis. Many of these signatures are also predictive of outcome in women who have not been treated with tamoxifen and so are markers of intrinsic biology rather than specific to tamoxifen responsiveness. Gene expression signatures representing particular biological processes (for example, cell cycle progression, cell death and invasion) or pathways (for example, RB deregulation, MYC overexpression and E2f activation) can also predict outcome in women treated with tamoxifen and point towards possible mechanisms for endocrine resistance. Functional genetic screens have successfully identified several genes, the loss or overexpression of which can reduce anti-oestrogen sensitivity in cell lines and is associated with clinical endocrine resistance. Insights into the mechanisms of resistance have suggested possible therapeutic approaches for endocrine-resistant ER-positive breast cancer, for example tyrosine kinase inhibitors. Further potential therapeutic targets may emerge from combining large-scale genomic and transcriptomic data with large-scale functional analyses. The efficacy of endocrine therapies (such as tamoxifen) in breast cancer is limited by intrinsic and acquired therapeutic resistance. What do we know about the genetic lesions and molecular processes that determine endocrine resistance in the clinic, and how can we use this to improve therapy? Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candi