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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 4

Elevated levels of oxidative stress following oncogene inactivation.

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Elevated levels of oxidative stress following oncogene inactivation.
(A)...
(A) Staining of organoid cultures with oxidative stress indicator DCFDA (green), superoxide specific MitoSox (red), and DAPI (gray). Single channel and merged representative images of never-induced (control), MYC/KRAS and MYC/NEU structures, and MYC/KRAS structures treated with N-acetylcysteine (NAC). Images are representative of triplicate experiments. Scale bar: 14 μm. (B) FACS was performed on regressed and control mice. To control for possible doxycycline effects, mice lacking the reverse tetracycline transactivator were used and placed in experimental cages along with the experimental mice and placed on a diet of chow containing doxycycline. When experimental mice developed a total tumor load of 2 cm3, all animals, experimental and control, were placed back on normal chow. Animals were maintained on doxycycline-free chow for > 8 weeks before being sacrificed for analysis. Red circles, mammary tumors; white circles, regressed tissue. (C) DCFDA was added to previously published FACS-based protocols for separation of mammary epithelial subpopulations. Upper panel: Representative FACS separation of subpopulations using previously published combination of CD29/CD24/CD49f for control, and MYC/KRAS and MYC/NEU regressed mice. Lower panel: Representative histograms the mean fluorescent intensities (MFI) of DCFDA in mammary epithelial cells isolated from age-matched control and regressed animals for the CD29hi/CD24hi/CD49fmed (luminal progenitors), CD29hi/CD24med/CD49fmed (myoepithelial), and CD29hi/CD24med/CD49fhi (Stem) populations. These results were representative for n = 9 (control), n = 3 (MYC/NEU), and n = 6 (MYC/KRAS) independent experiments. (D) Quantification of fold-change of MFI for DCFDA over age-matched control. Parous animals were included as a control for inflammation-driven oxidative stress. Luminal progenitors: MYC/KRAS vs. control, P = 0.0006; MYC/NEU vs. control, P = 0.002. Myoepithelial: MYC/KRAS vs. control, P = 0.0003; MYC/NEU vs. control, P = 0.03. Stem: MYC/KRAS vs. control, P = 0.0084 enriched populations. One sample t test. Data represented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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