Clonal heterogeneity in ER+ breast cancer reveals the proteasome and PKC as potential therapeutic targets.

Autor: Beumers L; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. lukas.beumers@gmail.com.; Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany. lukas.beumers@gmail.com., Vlachavas EI; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Borgoni S; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Schwarzmüller L; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.; Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany., Penso-Dolfin L; Division of Somatic Evolution and Early Detection, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Michels BE; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Sofyali E; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Burmester S; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Heiss D; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Wilhelm H; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Yarden Y; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, 76100, Israel., Helm D; Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Will R; Cellular Tools Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Goncalves A; Division of Somatic Evolution and Early Detection, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany., Wiemann S; Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. s.wiemann@dkfz-heidelberg.de.; Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany. s.wiemann@dkfz-heidelberg.de.
Jazyk: angličtina
Zdroj: NPJ breast cancer [NPJ Breast Cancer] 2023 Dec 02; Vol. 9 (1), pp. 97. Date of Electronic Publication: 2023 Dec 02.
DOI: 10.1038/s41523-023-00604-4
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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