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Figure 1. Spectrum of ESR1 alterations found in metastatic ER+ breast cancer. ER+ breast cancer cells that have spread beyond the breast to metastatic sties have been found to express wild-type ESR1 or harbor a variety of ESR1 alterations. A: Metastatic tumors can express wild-type estrogen receptor alpha protein (ERa), which is encoded by the estrogen receptor alpha gene (ESR1) located on chromosome (chr) 6. ESR1 transcripts are generated from 2 non-coding exons (e) depicted by white boxes and 8 coding exons depicted by gray shaded boxes; B: Metastatic ER+ tumors may also harbor amplification of ESR1 resulting in multiple copies of ESR1 and increased ER protein expression; C: Point mutations that cluster within the ligand-binding domain (LBD) of ESR1 that confer constitutive ligand-independent activation of ESR1 mutants have also been well-described in metastatic ER+ breast tumors, especially those which had been extensively pretreated with Als; D: Emerging studies have now identified structural rearrangements involving ESR1 that generate in-frame ESR1 fusion transcripts. In-frame fusion transcripts that retain the first 6 exons of ESR1 (ESR1-e6) produce stable ESR1 fusion proteins have been shown to be transcriptionally active and drive endocrine therapy resistance and metastasis in ER+ breast cancer. AF1: activation function 1 domain; DBD: DNA-binding domain; AF2: activation function 2 domain; aa: amino acid