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Cadmium activation of wild-type and constitutively active estrogen receptor alpha.
Psaltis, John B; Wang, Qiaochu; Yan, Gai; Gahtani, Reem; Huang, Nanxi; Haddad, Bassem R; Martin, Mary Beth.
Afiliación
  • Psaltis JB; Department of Oncology, Georgetown University, Washington, DC, United States.
  • Wang Q; Depatment of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States.
  • Yan G; Department of Oncology, Georgetown University, Washington, DC, United States.
  • Gahtani R; Depatment of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States.
  • Huang N; Department of Oncology, Georgetown University, Washington, DC, United States.
  • Haddad BR; Department of Oncology, Georgetown University, Washington, DC, United States.
  • Martin MB; Department of Oncology, Georgetown University, Washington, DC, United States.
Front Endocrinol (Lausanne) ; 15: 1380047, 2024.
Article en En | MEDLINE | ID: mdl-39184142
ABSTRACT
The estrogen receptor alpha (ERα) plays a central role in the etiology, progression, and treatment of breast cancers. Constitutively activating somatic mutations Y537S and D538G, in the ligand binding domain (LBD) of ESR1, are associated with acquired resistance to endocrine therapies. We have previously shown that the metalloestrogen calcium activates ERα through an interaction with the LBD of the receptor. This study shows that cadmium activates ERα through a mechanism similar to calcium and contributes to, and further increases, the constitutive activity of the ERα mutants Y537S and D538G. Mutational analysis identified C381, N532A, H516A/N519A/E523A, and E542/D545A on the solvent accessible surface of the LBD as possible calcium/metal interaction sites. In contrast to estradiol, which did not increase the activity of the Y537S and D538G mutants, cadmium increased the activity of the constitutive mutants. Mutation of the calcium/metal interaction sites in Y537S and D538G mutants resulted in a significant decrease in constitutive activity and cadmium induced activity. Mutation of calcium/metal interaction sites in wtERα diminished binding of the receptor to the enhancer of estrogen responsive genes and the binding of nuclear receptor coactivator 1 and RNA polymerase II. In contrast to wtERα, mutation of the calcium/metal interaction sites in the Y537S and D538G mutants did not diminish binding to DNA but prevented a stable interaction with the coactivator and polymerase. Growth assays further revealed that calcium channel blockers and chelators significantly decreased the growth of MCF7 cells expressing these constitutively active mutants. Taken together, the results suggest that exposure to cadmium plays a role in the etiology, progression, and response to treatment of breast cancer due, in part, to its ability to activate ERα.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cadmio / Receptor alfa de Estrógeno Límite: Female / Humans Idioma: En Revista: Front Endocrinol (Lausanne) Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cadmio / Receptor alfa de Estrógeno Límite: Female / Humans Idioma: En Revista: Front Endocrinol (Lausanne) Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza