Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.
Proc Natl Acad Sci U S A
; 115(31): 7869-7878, 2018 07 31.
Article
em En
| MEDLINE
| ID: mdl-29987050
ABSTRACT
Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Receptores de Estrogênio
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Estrogênios
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Proteínas de Neoplasias
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article