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

Dina Hany, Vasiliki Vafeiadou, Didier Picard
doi: https://doi.org/10.1101/2022.06.03.494664
Dina Hany
Département de Biologie Moléculaire et Cellulaire Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH - 1211 Genève 4, Switzerland
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Vasiliki Vafeiadou
Département de Biologie Moléculaire et Cellulaire Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH - 1211 Genève 4, Switzerland
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Didier Picard
Département de Biologie Moléculaire et Cellulaire Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH - 1211 Genève 4, Switzerland
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  • For correspondence: didier.picard@unige.ch
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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+ 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 Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 03, 2022.
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CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells
Dina Hany, Vasiliki Vafeiadou, Didier Picard
bioRxiv 2022.06.03.494664; doi: https://doi.org/10.1101/2022.06.03.494664
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CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells
Dina Hany, Vasiliki Vafeiadou, Didier Picard
bioRxiv 2022.06.03.494664; doi: https://doi.org/10.1101/2022.06.03.494664

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