Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-07, Vol.115 (31), p.7869-7878
• Main Authors: Xiao, Tengfei, Li, Wei, Wang, Xiaoqing, Xu, Han, Yang, Jixin, Wu, Qiu, Huang, Ying, Geradts, Joseph, Jiang, Peng, Fei, Teng, Chi, David, Zang, Chongzhi, Liao, Qi, Rennhack, Jonathan, Andrechek, Eran, Li, Nanlin, Detre, Simone, Dowsett, Mitchell, Jeselsohn, Rinath M., Liu, Shirley, Brown, Myles
• Format: Article
• Language: English
• Subjects: Biological Sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer therapies; Endocrine therapy; Estrogen receptors; Estrogens; Estrogens - pharmacology; Feedback; Feedback loops; Female; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; GTP-binding protein; Humans; INAUGURAL ARTICLE; Kinases; MCF-7 Cells; Negative feedback; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; p21-Activated Kinases - biosynthesis; p21-Activated Kinases - genetics; Proteins; Receptors, Estrogen - biosynthesis; Receptors, Estrogen - genetics; src-Family Kinases - biosynthesis; src-Family Kinases - genetics; Therapy; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1722617115

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.