The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells Journal Article

   

Authors:	Fanning, S. W.; Jeselsohn, R.; Dharmarajan, V.; Mayne, C. G.; Karimi, M.; Buchwalter, G.; Houtman, R.; Toy, W.; Fowler, C. E.; Han, R.; Lainé, M.; Carlson, K. E.; Martin, T. A.; Nowak, J.; Nwachukwu, J. C.; Hosfield, D. J.; Chandarlapaty, S.; Tajkhorshid, E.; Nettles, K. W.; Griffin, P. R.; Shen, Y.; Katzenellenbogen, J. A.; Brown, M.; Greene, G. L.
Article Title:	The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells
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. © 2018, Fanning et al.
Keywords:	breast cancer; estrogen receptor; hormone therapy; cancer biology; human; acquired drug resistance; esr1 somatic mutation; selective estrogen receptor degrader
Journal Title:	eLife
Volume:	7
ISSN:	2050-084X
Publisher:	eLife Sciences Publications Ltd.
Date Published:	2018-11-29
Start Page:	e37161
Language:	English
DOI:	10.7554/eLife.37161
PUBMED:	30489256
PROVIDER:	scopus
PMCID:	PMC6335054
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060022516&doi=10.7554%2feLife.37161&partnerID=40&md5=e82c60ab46847c1a651a6442bbeab5e7
Notes:	Export Date: 1 February 2019 -- Source: Scopus

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