Ariadne Genomics Inc. tamoxifen membrane tethered ERs - rapid, non-genomic effects endoxifen 4-OH-TAM breast neoplasms Esr1 Esr2 estrogen signaling pathway supressed target gene expression ---| breast neoplasms tamoxifen pharmacokinetics pathway Ncoa3 --+> Esr1 Esr1 ---> tamoxifen resistance 4-OH-TAM ---- Esr2 endoxifen ---- Esr1 Esr2 ---- tamoxifen Esr1 ---- tamoxifen Ncoa3 mERs ---> tamoxifen resistance mERs endoxifen ---- Esr2 4-OH-TAM ---- Esr1 drug-bound ER corepressors ---| Esr1 tamoxifen resistance tumor growth supressed target gene expression Esr2 ---| supressed target gene expression Esr1 ---- Ncoa3 supressed target gene expression ---| tumor growth Esr1 ---| supressed target gene expression mERs ---- tamoxifen drug-bound ER corepressors ---- Esr1 drug-bound ER corepressors