Clonal heterogeneity in ER+ breast cancer reveals the proteasome and PKC as potential therapeutic targets
Intratumoral heterogeneity impacts the success or failure of anti-cancer therapies. Here, we investigated the evolution and mechanistic heterogeneity in clonal populations of cell models for estrogen receptor positive breast cancer. To this end, we established barcoded models of luminal breast cance...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
02 December 2023
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| In: |
npj Breast cancer
Year: 2023, Volume: 9, Issue: 1, Pages: 1-15 |
| ISSN: | 2374-4677 |
| DOI: | 10.1038/s41523-023-00604-4 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41523-023-00604-4 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41523-023-00604-4 
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| Author Notes: | Lukas Beumers, Efstathios-Iason Vlachavas, Simone Borgoni, Luisa Schwarzmüller, Luca Penso-Dolfin, Birgitta E. Michels, Emre Sofyali, Sara Burmester, Daniela Heiss, Heike Wilhelm, Yosef Yarden, Dominic Helm, Rainer Will, Angela Goncalves and Stefan Wiemann |
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| 520 | |a Intratumoral heterogeneity impacts the success or failure of anti-cancer therapies. Here, we investigated the evolution and mechanistic heterogeneity in clonal populations of cell models for estrogen receptor positive breast cancer. To this end, we established barcoded models of luminal breast cancer and rendered them resistant to commonly applied first line endocrine therapies. By isolating single clones from the resistant cell pools and characterizing replicates of individual clones we observed inter- (between cell lines) and intra-tumor (between different clones from the same cell line) heterogeneity. Molecular characterization at RNA and phospho-proteomic levels revealed private clonal activation of the unfolded protein response and respective sensitivity to inhibition of the proteasome, and potentially shared sensitivities for repression of protein kinase C. Our in vitro findings are consistent with tumor-heterogeneity that is observed in breast cancer patients thus highlighting the need to uncover heterogeneity at an individual patient level and to adjust therapies accordingly. | ||
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