Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Lipid Metabolism Reprogramming Is Associated with Trastuzumab Resistance in ERBB2+ Breast Cancer Cell Lines

Katia Cortese
* ORCID logo ,
Marco Ponassi
,
Aldo Profumo
,
Gabriela Coronel Vargas
ORCID logo ,
Erika Iervasi
,
Maria Cristina Gagliani
,
Grazia Bellese
,
Sara Tavella
,
Patrizio Castagnola
*
Version 1 : Received: 31 March 2023 / Approved: 3 April 2023 / Online: 3 April 2023 (02:19:25 CEST)

How to cite: Cortese, K.; Ponassi, M.; Profumo, A.; Coronel Vargas, G.; Iervasi, E.; Gagliani, M. C.; Bellese, G.; Tavella, S.; Castagnola, P. Lipid Metabolism Reprogramming Is Associated with Trastuzumab Resistance in ERBB2+ Breast Cancer Cell Lines. Preprints 2023, 2023040002. https://doi.org/10.20944/preprints202304.0002.v1 Cortese, K.; Ponassi, M.; Profumo, A.; Coronel Vargas, G.; Iervasi, E.; Gagliani, M. C.; Bellese, G.; Tavella, S.; Castagnola, P. Lipid Metabolism Reprogramming Is Associated with Trastuzumab Resistance in ERBB2+ Breast Cancer Cell Lines. Preprints 2023, 2023040002. https://doi.org/10.20944/preprints202304.0002.v1

Abstract

The antibody Trastuzumab (Tz) targeting ERBB2 has improved the prognosis of patients with breast cancer (BCa) that overexpress this receptor. Resistance to Tz negatively impacts prognosis. Several mechanisms have been reported to cause Tz resistance. The objective of this study was to identify common mechanisms in in vitro models of acquired BCa Tz resistance. In particular, we used three widely available ERBB2+ BCa cell lines adapted to grow in Tz. We performed several analyses to address possible changes in phenotype, proliferation, and ERBB2 membrane expres-sion common to the three Tz-R cell lines compared to wt, but none was found. High-resolution mass spectrometry analysis identified, instead, a common set of differentially expressed proteins (DEPs) in Tz-R vs. wt cells. Furthermore, bioinformatic tools revealed that all three Tz-R cell models shared a modulation of proteins involved in the metabolism of lipids, organophosphate biosynthetic process, and macromolecule methylation. Ultrastructural analysis confirmed altera-tion of lipid droplets in resistant cells. Our data strongly support the hypothesis that complex metabolic adaptation, including lipid metabolism, protein phosphorylation, and possibly chro-matin remodeling, may fuel Tz resistance. The identification of a common set of 10 DEPs in all three TZ-resistant cell lines may provide novel targets for therapeutic intervention.

Keywords

trastuzumab; trastuzumab resistance; HER2; breast cancer; proteomic analysis; metabolic reprogramming.

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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