@article {613953, title = {Estrogen-regulated feedback loop limits the efficacy of estrogen receptor{\textendash}targeted breast cancer therapy}, journal = {Proceedings of the National Academy of Sciences}, year = {2018}, abstract = {Estrogen receptor-positive (ER+) breast cancer is treated with endocrine therapies, although therapeutic resistance almost invariably develops in advanced disease. Using genome-wide CRISPR screens, we identified genes whose loss confers endocrine resistance, as well as synthetic lethal vulnerabilities to overcome such resistance. These findings reveal an estrogen-induced negative feedback loop that constrains the growth of ER+ tumors, thereby limiting the efficacy of therapies that inhibit ER, and suggest a previously unappreciated therapeutic route to overcoming endocrine resistance.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.}, doi = {10.1073/pnas.1722617115}, url = {http://www.pnas.org/content/pnas/early/2018/07/06/1722617115.full.pdf}, author = {Xiao, Tengfei and Li, Wei and Xiaoqing Wang and Han Xu and Jixin Yang and Wu, Qiu and Huang, Ying and Geradts, Joseph and Jiang, Peng and Teng Fei and Chi, David and Zang, Chongzhi and Qi Liao and Rennhack, Jonathan and Eran Andrechek and Li, Nanlin and Detre, Simone and Dowsett, Mitchell and Rinath M. Jeselsohn and X. Shirley Liu and Brown, Myles} }