Table 1 |.

Common molecular mechanisms of endocrine resistance in breast cancer

Route of resistance	Mechanism	Examples	Mutation prevalence
Retain ER signalling in the presence of ER-pathway-targeted endocrine therapies	Acquisition of ligand-independent ESR1 mutations	LBD or activating ESR1 mutations	0–5% pre-ET, 30–40% post-ET
		ESR1 in-frame fusions with partner genes (e.g., YAP1)	0–2%
	Alterations in the ratio of ER-associated co-regulatory proteins	Elevated expression of co-activators, such as NCOA1 and NCOA3	Not applicable
		Loss of co-repressors, such as N-CoR1 and N-CoR2
Activation and acquired dependency of alternative proliferative pathways	Acquired ERBB2 activity and dependency	ERBB2 amplification; occurs before endocrine therapies and confers intrinsic resistance	~5%
		ERBB2 mutations; acquired following endocrine therapy	1–2% pre-ET, 5–10% post-ET
	Acquired activity and dependency on other receptor tyrosine kinases (RTKs) and downstream MAPK signalling	Amplification of EGFR	1–5% per alteration
		Co-amplification of FGFR1 and associated factors
		Loss-of-function mutations in negative regulators of the MAPK pathway (e.g., NF1)
		Activating mutations in positive regulators of the MAPK pathway (e.g., KRAS, BRAF and MAP2K1)
Broader alterations in the landscape of transcriptional regulators	Mutations in other key transcription factors	Amplifications and hotspot mutations in MYC and CTCF	1–10% per alteration
		FOXA1 mutations in the Wing2-region; proposed to enhance ER-mediated transcription
		FOXA1 mutations (e.g., SY242CS), which activate alternative transcriptomes via non-canonical DNA binding
	Decrease or loss of ER expression, possibly owing’ to lineage plasticity (as in prostate cancer)	Abnormal DNA methylation of the ER CpG island	Not applicable
		Chromatin inactivation by histone deacetylation
		Repression of ESR1 transcription via Twist

Major routes of endocrine resistance, along with examples of specific mechanisms. For mechanisms driven by genomic alterations, literature-reported prevalences are shown. (Disparities in publicly available data sets — for example, assay, sampling method and so on — make it difficult to align mutational frequencies across studies; such meta-analyses are beyond the scope of this Review.) EGFR, epidermal growth factor receptor; ER, oestrogen receptor; ERBB2, erb-b2 receptor tyrosine kinase 2; ESR1, oestrogen receptor 1; ET, endocrine therapy; FGFR1, fibroblast growth factor receptor 1; LBD, ligand-binding domain; MAPK, mitogen-activated protein kinase; NCOA1, nuclear receptor co-activator 1 (also known as SRC1); N-CoR, nuclear receptor co-repressor; NF1, neurofibromin 1; YAP1, Yes1-associated transcriptional regulator.