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Metabolic shifts in residual breast cancer drive tumor recurrence
Kristina M. Havas, … , Rocio Sotillo, Martin Jechlinger
Kristina M. Havas, … , Rocio Sotillo, Martin Jechlinger
Published May 15, 2017
Citation Information: J Clin Invest. 2017;127(6):2091-2105. https://doi.org/10.1172/JCI89914.
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Research Article Metabolism Oncology

Metabolic shifts in residual breast cancer drive tumor recurrence

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Abstract

Tumor recurrence is the leading cause of breast cancer–related death. Recurrences are largely driven by cancer cells that survive therapeutic intervention. This poorly understood population is referred to as minimal residual disease. Here, using mouse models that faithfully recapitulate human disease together with organoid cultures, we have demonstrated that residual cells acquire a transcriptionally distinct state from normal epithelium and primary tumors. Gene expression changes and functional characterization revealed altered lipid metabolism and elevated ROS as hallmarks of the cells that survive tumor regression. These residual cells exhibited increased oxidative DNA damage, potentiating the acquisition of somatic mutations during hormonal-induced expansion of the mammary cell population. Inhibition of either cellular fatty acid synthesis or fatty acid transport into mitochondria reduced cellular ROS levels and DNA damage, linking these features to lipid metabolism. Direct perturbation of these hallmarks in vivo, either by scavenging ROS or by halting the cyclic mammary cell population expansion, attenuated tumor recurrence. Finally, these observations were mirrored in transcriptomic and histological signatures of residual cancer cells from neoadjuvant-treated breast cancer patients. These results highlight the potential of lipid metabolism and ROS as therapeutic targets for reducing tumor recurrence in breast cancer patients.

Authors

Kristina M. Havas, Vladislava Milchevskaya, Ksenija Radic, Ashna Alladin, Eleni Kafkia, Marta Garcia, Jens Stolte, Bernd Klaus, Nicole Rotmensz, Toby J. Gibson, Barbara Burwinkel, Andreas Schneeweiss, Giancarlo Pruneri, Kiran R. Patil, Rocio Sotillo, Martin Jechlinger

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Figure 5

Inhibitors of lipid metabolism abrogate oxidative DNA damage in regressed cells.

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Inhibitors of lipid metabolism abrogate oxidative DNA damage in regresse...
(A) Confocal microscopy imaging of control and regressed mammary tissue stained for FASN (cyan), 8-hydrox-deGuaninine (8-OHdG; red), and DAPI (gray). Scale bar: 15 μm. (B) To causally link lipid metabolism to oxidative stress, organoid cultures were treated with C75 or etomoxir after oncogene withdrawal with 100 μm etomoxir or 0.6 μg/ml C75 for 24 hours. Following a 24-hour incubation, cells were assessed by DCFDA (FACS) and/or subjected to aldehyde reactive probe (ARP) assay (see below). (C) FACS of cells derived from treated organoid cultures. Upper panels: Representative histograms showing the difference in DCFDA control (gray) and regressed (black) organoids derived from MYC/KRAS and MYC/NEU mice. Middle panels: Representative histograms of control samples (gray) treated with C75 (blue) and etomoxir (red). Lower panels: Representative histograms of regressed samples (black) treated with C75 (blue) and etomoxir (red). Mean fold-change for (n = 3) control and (n = 4) regressed independent experiments is represented on the right. Regressed (P = 0.0189); regressed + C75 (P < 0.0001); regressed + etomoxir (P < 0.0001). One-way ANOVA with Sidak multiple comparison test. (D) ARP assay for base-excision repair intermediates. Detection of the apurinic/apyrimidinic sites is achieved through use of a biotinylated probe that binds the exposed aldehyde present in the AP site. Quantification is done using streptavidin-HRP. (E) Quantification of ARP assay represented as fold-change of ARP incorporated into the DNA isolated from C75- and etomoxir-treated and untreated regressed organoids (n = 2) and control (n = 2) untreated organoid cultures. Regressed + C75 (P = 0.0019); regressed + etomoxir (P = 0.0014). One-way ANOVA with Dunnetts multiple comparison test. (F) Quantification ARP assay represented as fold-change of ARP incorporated into the DNA isolated from experimental animals over age-matched controls. Represented for MYC/KRAS (P = 0.025), n = 4; MYC/NEU (P = 0.036), n = 3; control, n = 4 animals; one sample t test. Data represented as mean ± SEM; *P < 0.05, **P < 0.01, ****P < 0.0001.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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