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Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming
2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
2nd Department of Internal Medicine, Athens Naval and Veterans Hospital, Athens, Greece.
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2023 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, no 1, article id 169Article in journal (Refereed) Published
Abstract [en]

Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.

Methods: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.

Results: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.

Conclusions: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023. Vol. 21, no 1, article id 169
Keywords [en]
Breast cancer, Caloric restriction, Fasting, Metabolic reprogramming, Mitochondria, Oncological treatment, Oxidative stress, Reactive oxygen species, Starvation, Triple negative breast cancer
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-205797DOI: 10.1186/s12967-023-03935-9ISI: 000943526300004PubMedID: 36869333Scopus ID: 2-s2.0-85149714467OAI: oai:DiVA.org:umu-205797DiVA, id: diva2:1746377
Funder
The Kempe Foundations, JCK-1526The Kempe Foundations, KCK-1620Swedish Research Council, 2021-00960Swedish Cancer Society, 2017/315The Kempe Foundations, JCK-1826Cancerforskningsfonden i Norrland, AMP20-993Cancerforskningsfonden i Norrland, AMP 17-884Available from: 2023-03-28 Created: 2023-03-28 Last updated: 2023-03-28Bibliographically approved

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Williams, ChloeZhang, WeiNordström, AndersGilthorpe, Jonathan D.Frisan, Teresa

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Department of Integrative Medical Biology (IMB)Department of Plant PhysiologyUmeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Medicine)Department of Molecular Biology (Faculty of Science and Technology)
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