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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • July 31, 2018

Published In

Volume / Issue

  • 115 / 31

Start / End Page

  • 7869 - 7878

PubMed ID

  • 29987050

Pubmed Central ID

  • PMC6077722

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1722617115


  • eng

Conference Location

  • United States