Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.

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 inhib

SUBMITTER: Xiao T 

PROVIDER: S-EPMC6077722 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature