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

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

  • NPJ Breast Cancer. 2023 Dec 2;9(1):97. doi: 10.1038/s41523-023-00604-4.
Lukas Beumers 1 2,  Efstathios-Iason Vlachavas 3,  Simone Borgoni 3,  Luisa Schwarzmüller 3 4,  Luca Penso-Dolfin 5,  Birgitta E Michels 3,  Emre Sofyali 3,  Sara Burmester 3,  Daniela Heiss 3,  Heike Wilhelm 3,  Yosef Yarden 6,  Dominic Helm 7,  Rainer Will 8,  Angela Goncalves 5,  Stefan Wiemann 9 10
Affiliations

Affiliations

  • 1 Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. [email protected].
  • 2 Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany. [email protected].
  • 3 Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
  • 4 Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany.
  • 5 Division of Somatic Evolution and Early Detection, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
  • 6 Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
  • 7 Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
  • 8 Cellular Tools Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
  • 9 Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. [email protected].
  • 10 Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany. [email protected].
PMID: 38042915 DOI: 10.1038/s41523-023-00604-4
Abstract

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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