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Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.
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.
Duke Scholars
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Related Subject Headings
- src-Family Kinases
- p21-Activated Kinases
- Receptors, Estrogen
- Neoplasm Proteins
- MCF-7 Cells
- Humans
- Gene Expression Regulation, Neoplastic
- Gene Expression Regulation, Enzymologic
- Female
- Estrogens
Citation
![Journal cover image](https://secure.syndetics.com/index.aspx?isbn=/lc.gif&issn=1091-6490&client=dukeuniv)
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- src-Family Kinases
- p21-Activated Kinases
- Receptors, Estrogen
- Neoplasm Proteins
- MCF-7 Cells
- Humans
- Gene Expression Regulation, Neoplastic
- Gene Expression Regulation, Enzymologic
- Female
- Estrogens