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

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 6

Progesterone antagonists and ROS scavengers attenuate tumor recurrence.

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Progesterone antagonists and ROS scavengers attenuate tumor recurrence. ...
(A) The nonpregnant adult mammary gland undergoes profound morphological changes during the ovarian estrous cycle. A specific 2-fold expansion of the alveolar branching coincides with the peak in progesterone during diestrus. The hormone-driven induction of proliferation can be recapitulated in vitro through serial reseeding of organoid cultures. Reseeding of singularized cells stimulates de novo proliferation, resulting in the formation of acinar structures, similar to initial acini formation. (B) Generation of in vitro relapses through continuous reseeding of singularized cells. Represented as relapse-free persistence for never-induced, regressed, and regressed + N-acetylcysteine (NAC) (20 μM) populations; n = 6 independent experiments. Lower panel: Representative brightfield images of acinar structures from serially reseeded cultures at the third reseeding for hollow never-induced structures and corresponding regressed structures with first appearance of in vitro relapse. Scale bar: 50 μm. (C) Attenuation of tumor recurrence following treatment with progesterone antagonists and ROS scavengers. Upper panel: Experimental timeline in which MYC/KRAS regressed mice were treated with NAC, mifepristone, or the combination of NAC/mifepristone. Treatment began 2 weeks following oncogene inactivation and continued until spontaneous recurrence or 80 weeks after oncogene inactivation. Lower left panel: Role of mifepristone, a progesterone-receptor modulator that blocks hormone-driven expansion of the mammary gland. We postulated that cessation of proliferation would result in a decrease in somatic mutations generated via replication through oxidative DNA adducts, subsequently lowering the rate of tumor recurrence. The survival curve (lower right) represents relapse-free survival percentages for the 4 cohorts of mice treated with NAC, mifepristone, or the combination of NAC/mifepristone, as well as control nontreated. Significance was calculated using the log-rank (Mantel-Cox) test confronting NAC cohort, P = 0.0342; mifepristone cohort, P = 0.0004; and NAC + mifepristone cohort, P = 0.0039 with untreated. No significant difference was seen noted between the 2 mifepristone containing cohorts P = 0.3995. *P < 0.05, **P < 0.01, ***P < 0.001.