CRISPR-Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells

In breast cancer, resistance to endocrine therapies that target estrogen receptor alpha (ER alpha), such as tamoxifen and fulvestrant, remains a major clinical problem. Whether and how ER alpha+ breast cancers switch from being estrogen -dependent to estrogen-independent remains unclear. With a genome-wide CRISPR-Cas9 knockout screen, we identified previously unknown biomarkers and potential therapeutic targets of endocrine resistance. We dem-onstrate that high levels of PAICS, an enzyme involved in the de novo biosynthesis of purines, can shift the balance of ER alpha activity to be more estrogen-independent and tamoxifen-resistant. We find that this may be due to elevated activities of cAMP-activated protein kinase A and mTOR, kinases known to phosphorylate ER alpha specifically and to stimulate its activity. Genetic or pharmacological targeting of PAICS sensitizes tamoxi-fen-resistant cells to tamoxifen. Addition of purines renders them more resistant. On the basis of these findings, we propose the combined targeting of PAICS and ER alpha as a new, effective, and potentially safe therapeu-tic regimen.