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Front. Genet. | doi: 10.3389/fgene.2018.00058

Growth of triple negative and progesterone positive breast cancer causes oxidative stress and down-regulates neuroprotective transcription factor NPAS4 and NPAS4-regulated genes in hippocampal tissues of TumorGraft mice – an aging connection

Anna Kovalchuk1, 2,  Yaroslav Ilnytskyy3, Rocio Rodriguez-Juarez3, Amanda Katz4,  David Sidransky4, 5,  Bryan Kolb1 and  Olga Kovalchuk3*
  • 1Department of Neuroscience, University of Lethbridge, Canada
  • 2Leaders in Medicine Program, Cumming School of Medicine, Canada
  • 3Biological Sciences, University of Lethbridge, Canada
  • 4Department of Oncology, Champions Oncology, United States
  • 5Department of Otolaryngology and Oncology, Johns Hopkins University, United States

While the refinement of existing and the development of new chemotherapeutic regimens has significantly improved cancer treatment outcomes and patient survival, chemotherapy still causes many persistent side effects. Central nervous system (CNS) toxicity is of particular concern, as cancer patients experience significant deficits in memory, learning, cognition, and decision-making. These chemotherapy-induced cognitive changes are termed chemo brain, and manifest in more than half of cancer survivors. Moreover, recent studies have emerged suggesting that neurocognitive deficits manifest prior to cancer diagnosis and treatment, and thus may be associated with tumor presence, a phenomenon recently termed ‘tumor brain’. To dissect the molecular mechanisms of tumor brain, we used TumorGraftTM models, wherein part of a patient’s tumor is grafted into immune-deficient mice.
Here, we analyzed molecular changes in the hippocampal tissues of mice carrying triple negative (TNBC) or progesterone receptor positive (PR+BC) xenografts. TNBC growth led to increased oxidative damage, as detected by elevated levels of 4-hydroxy-2-nonenal, a product of lipid peroxidation. Furthermore, the growth of TNBC and PR+BC tumors altered global gene expression in the murine hippocampus and affected multiple pathways implicated in PI3K-Akt and MAPK signalling, as well as other pathways crucial for the proper functioning of hippocampal neurons. TNBC and PR+BC tumor growth also led to a significant decrease in the levels of neuronal transcription factor NPAS4, a regulator that governs the expression of brain-derived neurotrophic factor (BDNF), and several other key brain neurotrophic factors and pro-survival molecules. The decreased expression of ERK1/2, NPAS4, and BDNF are also seen in neurodegenerative conditions and aging, and may constitute an important tumor brain mechanism.

Keywords: non-CNS cancer, Tumor brain, Brain ageing, Gene Expression, Animal Models

Received: 24 Nov 2017; Accepted: 08 Feb 2018.

Edited by:

Alexey Moskalev, Institute of Biology, Komi Scientific Center (RAS), Russia

Reviewed by:

George A. Garinis, Foundation for Research and Technology Hellas, Greece
Jing Dong, Baylor College of Medicine, United States  

Copyright: © 2018 Kovalchuk, Ilnytskyy, Rodriguez-Juarez, Katz, Sidransky, Kolb and Kovalchuk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Olga Kovalchuk, University of Lethbridge, Biological Sciences, 4401 University Drive, Lethbridge, T1K 3M4, AB, Canada,