RT Journal Article
SR Electronic
T1 CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.03.494664
DO 10.1101/2022.06.03.494664
A1 Hany, Dina
A1 Vafeiadou, Vasiliki
A1 Picard, Didier
YR 2022
UL http://biorxiv.org/content/early/2022/06/03/2022.06.03.494664.abstract
AB In breast cancer, resistance to endocrine therapies that target estrogen receptor α (ERα), such as tamoxifen and fulvestrant, remains a major clinical problem. Whether and how ERα+ breast cancers switch from being estrogen-dependent to -independent remains unclear. With a genome-wide CRISPR/Cas9 knockout screen, we identified new biomarkers and potential therapeutic targets of endocrine resistance. We demonstrate that high levels of PAICS, an enzyme involved in the de novo biosynthesis of purines, can shift the balance of ERα activity to be more estrogen-independent and tamoxifen-resistant. We indicate that this is due to an elevated activity of cAMP-activated protein kinase A and mammalian target of rapamycin, kinases known to phosphorylate ERα specifically and to stimulate its activity. Genetic or pharmacological targeting of PAICS sensitizes tamoxifen-resistant cells to tamoxifen. Based on these findings, we propose the combined targeting of PAICS and ERα as a new, effective, and potentially safe therapeutic regimen.Competing Interest StatementThe authors have declared no competing interest.