Significance: Bazedoxifene (BZA) is a potent orally available antiestrogen that is clinically 26 approved for use in hormone replacement therapy (DUAVEE). We explore the efficacy of BZA 27 to inhibit activating somatic mutants of ERα that can arise in metastatic breast cancers after 28 prolonged exposure to aromatase inhibitors or tamoxifen therapy. Breast cancer cell line, 29 biophysical, and structural data show that BZA disrupts helix 12 of the ERα ligand binding 30 domain to achieve improved potency against Y537S and D538G somatic mutants compared to 4-31 hydroxytamoxifen.Abstract 42 Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer 43 patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα) gene ligand-binding 44 domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with 45 improved efficacy versus tamoxifen might overcome the resistant phenotype in ER+ breast 46 cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in 47 hormone replacement therapies. We find BZA possesses improved inhibitory potency against the 48 Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in 49 combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and 50 structural biology studies show that BZA's selective estrogen receptor degrading (SERD) 51 properties that override the stabilizing effects of the Y537S and D538G ERα mutations. 52 53 54 55 56 57 58 59 60 Fanning, S.W. eLife 3 61 Introduction 62 Estrogen receptor alpha (ERα) plays critical roles in the etiology, treatment and 63 prevention of the majority of breast cancers [1]. Due to the high degree of efficacy and wide 64 therapeutic indices of endocrine therapies, patients may receive such treatments for progressive 65 disease over the course of several years [2]. Unfortunately, the majority of ER+ metastatic breast 66 cancers that initially respond to endocrine treatment will become refractory despite continued 67 ERα expression [2]. Selective estrogen receptor modulators (SERMs) like tamoxifen are 68 antagonistic in the breast and agonistic in the bone and endometrium. SERM agonist activity 69 stems from tissue-specific co-regulator binding in the presence of tamoxifen [3]. In addition, 70 somatic mutations to ESR1 (gene for ERα) ligand binding domain (LBD) were identified in 25-71 30% of patients who previously received endocrine treatment [2, 4-6]. Y537S and D538G are the 72 two most prevalent mutations, and pre-clinical studies show that these mutations confer 73 hormone-free transcriptional activity and relative resistance to tamoxifen and fulvestrant 74 treatment [2, 4-6]. Both mutants enable constitutive ERα activity by favoring the agonist-like 75 conformation of the receptor activating function-2 (AF-2) surface and significantly reduce 76 hormone and 4-hydroxytamoxifen (the active metabolite of tamoxifen) binding affinities [7, 8]. 77 Endocrine treatments with im...
The Creb‐Regulated Transcriptional Coactivator (Crtc) family of transcriptional coregulators drive Creb1‐mediated transcription effects on metabolism in many tissues, but the in vivo effects of Crtc2/Creb1 transcription on skeletal muscle metabolism are not known. Skeletal muscle‐specific overexpression of Crtc2 (Crtc2 mice) induced greater mitochondrial activity, metabolic flux capacity for both carbohydrates and fats, improved glucose tolerance and insulin sensitivity, and increased oxidative capacity, supported by upregulation of key metabolic genes. Crtc2 overexpression led to greater weight loss during alternate day fasting (ADF), selective loss of fat rather than lean mass, maintenance of higher energy expenditure during the fast and reduced binge‐eating during the feeding period. ADF downregulated most of the mitochondrial electron transport genes, and other regulators of mitochondrial function, that were substantially reversed by Crtc2‐driven transcription. Glucocorticoids acted with AMPK to drive atrophy and mitophagy, which was reversed by Crtc2/Creb1 signaling. Crtc2/Creb1‐mediated signaling coordinates metabolic adaptations in skeletal muscle that explain how Crtc2/Creb1 regulates metabolism and weight loss.
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