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.
journal_name
Proc Natl Acad Sci U S Aauthors
Xiao T,Li W,Wang X,Xu H,Yang J,Wu Q,Huang Y,Geradts J,Jiang P,Fei T,Chi D,Zang C,Liao Q,Rennhack J,Andrechek E,Li N,Detre S,Dowsett M,Jeselsohn RM,Liu XS,Brown Mdoi
10.1073/pnas.1722617115subject
Has Abstractpub_date
2018-07-31 00:00:00pages
7869-7878issue
31eissn
0027-8424issn
1091-6490pii
1722617115journal_volume
115pub_type
杂志文章abstract::The assembly and composition of human excision nuclease were investigated by electrophoretic mobility shift assay and DNase I footprinting. Individual repair factors or any combination of up to four repair factors failed to form DNA-protein complexes of high specificity and stability. A stable complex of high specific...
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