Affiliation:
1. Département de Biologie Moléculaire et Cellulaire, Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH - 1211 Genève 4, Switzerland.
2. On leave from: Department of Pharmacology and Therapeutics Faculty of Pharmacy, Pharos University in Alexandria, Alexandria 21311, Egypt.
Abstract
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
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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 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 find that this may be due to elevated activities of cAMP-activated protein kinase A and mTOR, kinases known to phosphorylate ERα specifically and to stimulate its activity. Genetic or pharmacological targeting of PAICS sensitizes tamoxifen-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 ERα as a new, effective, and potentially safe therapeutic regimen.
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
5 articles.
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