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

• DOI: 10.1073/pnas.1722617115
• Publication Date: 2018-07-09T19:18:23Z
• Authors: Tengfei Xiao; Wei Li; Xiaoqing Wang; Han Xu; Jixin Yang; Qiu Wu; Ying Huang; Joseph Geradts; Peng Jiang; Teng Fei; David Chi; Chongzhi Zang; Qi Liao; Jonathan Rennhack; Eran Andrechek; Nanlin Li; Simone Detre; Mitchell Dowsett; Rinath M. Jeselsohn; X. Shirley Liu; Myles Brown
• Keywords: Enzymologic; 0301 basic medicine; 570; Neoplastic; 610; Breast Neoplasms; Estrogens; Biological Sciences; Estrogen; Gene Expression Regulation, Enzymologic; Neoplasm Proteins; 3. Good health; CSK Tyrosine-Protein Kinase; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; src-Family Kinases; Gene Expression Regulation; Receptors, Estrogen; p21-Activated Kinases; Receptors; 616; MCF-7 Cells; Humans; Female

Significance

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.