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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.

ABSTRACT: 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 signaling, 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.

SUBMITTER: Kovalchuk A

PROVIDER: S-EPMC5845109 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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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.

Kovalchuk Anna A Ilnytskyy Yaroslav Y Rodriguez-Juarez Rocio R Katz Amanda A Sidransky David D Kolb Bryan B Kovalchuk Olga O

Frontiers in genetics 20180305

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 survi ...[more]

PMID: 29556248

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Project description:Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential.

Dataset Information

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.

Publications

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.

Similar Datasets

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