Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.
Journal Article (Journal Article)
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.
- 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, M
- July 31, 2018
Volume / Issue
- 115 / 31
Start / End Page
- 7869 - 7878
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States