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.

The relevance of pathophysiological alterations in redox signaling of 4-hydroxynonenal for pharmacological therapies of major stress-associated diseases

“…TumorGraft TM models of triplenegative breast cancer (TNBC) or progesterone receptor positive breast cancer (PR+BC) xenografts revealed implication of oxidative stress, and alteration of specific pathways (MAPK, PI3K/AKT) needed for the proper function of hippocampal neurons. While the decreased expression of AKT1, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), neuronal PAS domain protein 4, and brain-derived neurotrophic factor was observed in both TNBC and PR+BC tumor-bearing animals, increased levels of 4-HNE were seen just in TNBC tumor-bearing mice whereas the levels were decreased in PR+BC tumor-bearing mice [320].…”

Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review

“…Increased oxidative lipid damage (elevated levels of 4-hydroxy-2-nonenal) is observed in the hippocampal tissues of mice bearing triplenegative (TNBC) or progesterone receptor-positive (PR + BC) xenografts. In addition, TNBC and PR + BC tumor growth altered global gene expression in the hippocampus and affected multiple pathways [76]. An alteration of PI3K-Akt and MAPK signaling as well as other pathways crucial for the proper functioning of hippocampal neurons and a decrease in levels of the neuronal transcription factor NPAS4 [76], a regulator that governs the expression of brain-derived neurotrophic factor, a key brain neurotrophic factor crucial for cognitive functions [74,77,78].…”

“…In addition, TNBC and PR + BC tumor growth altered global gene expression in the hippocampus and affected multiple pathways [76]. An alteration of PI3K-Akt and MAPK signaling as well as other pathways crucial for the proper functioning of hippocampal neurons and a decrease in levels of the neuronal transcription factor NPAS4 [76], a regulator that governs the expression of brain-derived neurotrophic factor, a key brain neurotrophic factor crucial for cognitive functions [74,77,78]. The deleterious effects of cranial irradiation therapy, a technique widely used for cancer treatment, are accompanied by lipid peroxidation in the brain.…”

Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

“…The best found subgrouping (splice acceptor not on any exon or frameshift on 5th exon) is seen in a clear cluster of subgroupings which exhibit negative coefficients for a block of genes that are weighted positively in the gene-wide task. Of the five genes in this block that had the greatest differences in coefficient magnitude between these two tasks, only NPAS4 has not been previously assessed in the context of human breast cancers (though it has recently been a focus of murine breast cancer PDX models [ 51 ]). The remaining four have all been studied for their effects in the development and maintenance of human breast cancers (TNP1 [ 52 – 54 ], FST [ 55 ], ANKRD40 [ 56 ], TRH [ 57 , 58 ]).…”