Therapeutic resistance to anti-oestrogen therapy in breast cancer

Abstract

The hormone receptor oestrogen receptor-α (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20-40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the 'evolvability' of ER⁺ breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER⁺ breast cancers.

Fig. 1 |. Oestrogen receptor-α signalling and modes of inhibition.

Oestrogen receptor-α (ER) signalling can be inhibited via multiple therapeutic strategies. a, ER is a multidomain ligand-inducible transcription factor that when activated drives a transcriptional programme that supports progression through the cell cycle. b, Strategies for ER targeting that are clinically approved are shown on the top. Aromatase inhibitors, which deplete oestrogen via inhibition of CYP19A1, are also known to select for oestrogen-independent ESR1 mutations. Selective ER modulators inhibit the ligand-binding domain (LBD) but not DNA-binding domain (DBD) or activation function-1 (AF1) domain of ER. They can also act as a partial ER agonist in some contexts. Selective ER degraders inhibit both LBD and AF1 domains by preventing recruitment of co-activators, immobilizing and destabilizing ER, leading to degradation. Approaches for inhibiting ER that are currently under investigation are shown on the bottom. Covalent ER antagonists react to cysteine C530 in the ER ligand-binding pocket and enforce an antagonist conformation in both wild-type and mutant ER. ER-specific PROTACs recruit E3 ligase to the ER, promoting poly-ubiquitination and proteasomal degradation. (Note: ER forms a homodimer but is depicted here as a monomer for visual clarity). Ub, ubiquitin.

Fig. 2 |. Treatment of ER⁺ breast cancer with endocrine therapies creates a strong selective pressure that drives tumour evolution.

Tumours experiencing the pressure of endocrine therapies can evolve via distinct paths and can be categorized by their dependency on oestrogen receptor-α (ER) signalling (described from left to right below). Dark blue: a subset of cancers retain dependency on ER signalling but acquire features that render them resistant to first-line therapies such as aromatase inhibitors (AIs). The acquisition of ESR1 mutations exemplifies this evolution route, allowing tumours to progress in an ER-dependent but oestrogen-independent or other ligand-independent manner. These ER-dependent tumours are responsive to next-generation ER therapeutics, such as oral selective ER downregulators (SERDs). Yellow: tumours can also acquire alterations in other key transcription factors, such as FOXA1 or MYC. It remains unclear whether transcription factor-altered tumours retain ER dependency, thus further study is required to assess whether they might respond to next-generation ER-targeted therapies or require alternative treatments. Pink and red: other cancers lose dependency on ER altogether. Pink: of these, some become driven by orthogonal signalling pathways, such as HER2 or mitogen-activated protein kinases (MAPKs), and may benefit from the corresponding targeted therapies (for example, anti-HER2 therapies). Red: others lose ER expression altogether and show some evidence of undergoing lineage alterations. These tumours are reminiscent of lineage-plastic prostate cancers, which lose androgen receptor expression, although much less is known regarding lineage plasticity in breast cancer. Further investigation is required to devise treatment strategies for this subset. mBC, metastatic breast cancer; RTK, receptor tyrosine kinase.