Mechanism of disease
Disease mechanism in HR+, HER2− BC
ERα, the predominant ER isoform in BC (hereafter referred to as just ‘ER’) plays a critical role as the primary oncogenic driver in HR+, HER2– BC.1,2 Typically, oestrogen ligand (synthesised by a series of enzymes including aromatase) binds to the ER, activating ER-mediated signalling through nuclear (‘classical’) and non-nuclear (‘alternative’) pathways.1–4 However, ER-mediated signalling may also occur through ligand-independent mechanisms1-3 (see Endocrine resistance for more information).
Role of nuclear and non-nuclear ER signalling pathways in HR+, HER2− BC
In the nuclear pathway, the oestrogen–ER complex dimerises and translocates to the nucleus, binding DNA directly via oestrogen response elements, or indirectly via interaction with coregulator proteins, to induce transcription of a wide range of genes involved in cell proliferation and survival.1–4
In the non-nuclear pathway, oestrogen binds to ER at the plasma membrane or to G-protein-coupled ER, subsequently activating kinase signalling pathways (e.g. MAPK or the PI3K/AKT/mTOR) involved in cell proliferation and survival.1–4
References
- Brufsky AM & Dickler M, Oncologist 2018; 23:528–539;
- Fuentes N & Silveyra P, Adv Protein Chem Struct Biol 2019; 116:135–170;
- Clusan L, et al. Int J Mol Sci 2023; 24:6834;
- Miziak P, et al. Cancers (Basel) 2023; 15:4689.
