Abstract
Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.
Highlights
Estrogen receptor alpha (ERa) plays critical roles in the etiology, treatment and prevention of the majority of breast cancers (Frasor et al, 2004)
To assess the ability of BZA to inhibit WT ERa in breast cancer cells, we examined its impact on ERa transcriptional activity, degradation and cell growth in MCF-7 cells. 4-hydroxytamoxifen (4-OHT) was used as a representative Selective estrogen receptor modulators (SERMs) and FULV was used as a representative selective estrogen receptor degrading (SERD) (Figure 1)
Because BZA is already clinically approved for use in hormone replacement therapy and is a potent ERa antagonist in the breast, an agonist in bone, and neutral in the endometrium with long-term safety data in thousands of patients, we explored its ability to inhibit the Y537S and D538G ERa somatic mutants in breast cancer (Wardell et al, 2013a)
Summary
Estrogen receptor alpha (ERa) plays critical roles in the etiology, treatment and prevention of the majority of breast cancers (Frasor et al, 2004). Y537S and D538G are the two most prevalent mutations, and pre-clinical studies show that these mutations confer hormone-free transcriptional activity and relative resistance to tamoxifen and fulvestrant treatment (Toy et al, 2013; Jeselsohn et al, 2015; Jeselsohn et al, 2014; Niu et al, 2015) Both mutants enable constitutive ERa activity by favoring the agonist-like conformation of the receptor activating function-2 (AF-2) surface and significantly reduce hormone and 4-hydroxytamoxifen (the active metabolite of tamoxifen) binding affinities (Nettles et al, 2008; Fanning et al, 2016)
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