Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.
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Embargo End Date
ICR Authors
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
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
Document Type
Journal Article
Date
2018-07-09
Date Accepted
2018-06-15
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.
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (31), pp. 7869 - 7878
Source Title
Publisher
NATL ACAD SCIENCES
ISSN
0027-8424
eISSN
1091-6490
Collections
Research Team
Endocrinology