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The biological age linked with oxidative estress modifies breast cancer aggressiveness

ABSTRACT: The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes possibly share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, developed from genetically different ERBB2-positive transgenic mice generated by a backcross, is more aggressive in younger than in older mice, similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. This model included the serum levels of HDL-cholesterol and magnesium that were determined at a disease-free stage, and total AKT1 and glutathione concentrations in the liver at the time of necropsy. Later we defined the grade of aging due to oxidative stress as the increment of aging, which was the difference between the predicted biological age and the chronological age. This comparison permitted the identification of the biologically younger mice with less oxidative stress and older mice with more oxidative stress than would be expected according to their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. We identified genomic regions on chromosomes 2 and 15 that were linked to the grade of oxidative aging. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of oxidative aging and tumour aggressiveness. This study shows part of the complex interactions between breast cancer and aging.

ORGANISM(S): Mus musculus Mus

PROVIDER: GSE99962 | GEO | 2017/06/14

SECONDARY ACCESSION(S): PRJNA390241

REPOSITORIES: GEO

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Project description:Inadequate protein intake initiates an accommodative response with adverse changes in skeletal muscle function and structure. mRNA level changes due to short-term inadequate dietary protein might be an early indicator of accommodation. The aims of this study were to assess the effects of dietary protein and the diet-by-age interaction on the skeletal muscle transcript profile. Self-organizing maps were used to determine expression patterns across protein trials. 958 transcripts were differentially expressed (P<0.05) with diet and 853 had a diet-by-age interaction (P<0.05) using ANOVA. The results for diet alone revealed that P63 was associated with up-regulation of transcripts related to ubiquitin-dependent protein catabolism and muscle contraction and P63 and P94 resulted in up-regulation of transcripts related to apoptosis and down-regulation of transcripts related to cell differentiation; muscle and organ development; extracellular space; and responses to stimuli and stress. The diet-by-age expression patterns demonstrated that across the three protein trials transcripts related to protein metabolism were affected by age. Changes in skeletal muscle mRNA levels in the younger and older males to protein intake near or below the RDA are indicative of an early accommodative response. 5052 transcripts were determined as differentially expressed (P<0.05) between the younger and older males, of which 2556 met the False Discovery Rate correction (P=0.0081). The age-related changes in the transcript profile were consistent with aging skeletal muscle phenotypes including; mitochondrial dysfunction (UP- and DOWN-regulation), RNA splicing (UP), oxidative stress (UP), apoptosis (UP), and energy metabolism (DOWN). Experiment Overall Design: 22 healthy free-living younger (21-43 y, n=12) and older (63-79 y, n=10) males completed three controlled feeding trials with protein intakes of 63% (P63: 0.50 g/kg), 94% (P94: 0.75 g/kg), and 125% (P125: 1.00 g/kg) of the recommended dietary allowance (RDA). A fasting state vastus lateralis biopsy was taken from the dominant leg of each subject on day 12 of each trial following an overnight fast. Total RNA was isolated from the muscle samples using Tri-Reagent and the manufacture's protocol.

Project description:Calorie restriction (CR) enhances longevity and mitigates aging phenotypes in numerous species. Physiological responses to CR are cell-type specific and variable throughout the lifespan; however, the mosaic of molecular changes responsible CR benefits remain unclear, particularly in brain regions susceptible to deterioration throughout aging. Thus, we examined the influence of long-term CR on the CA1 hippocampal region, a key learning and memory brain area that is vulnerable to age-related pathologies, such as Alzheimerâs disease (AD). Through mRNA sequencing and NanoString nCounter analysis, we demonstrate that one year of CR feeding suppresses an age-dependent signature of 882 genes functionally associated with synaptic transmission-related pathways, including calcium signaling, long-term potentiation (LTP), and Creb signaling in wild-type mice. By comparing the influence of CR on hippocampal CA1 region transcriptional profiles at younger- (5 months) and older-adult (15 months) timepoints, we identify conserved upregulation of proteome quality control and calcium buffering genes, including heat shock 70 kDa proteins 1b and 5 (Hspa1b and Hspa5), protein disulfide isomerase family A members 4 and 6 (Pdia4 and Pdia6), and calreticulin (Calr). Expression levels of putative neuroprotective factors, klotho (Kl) and transthyretin (Ttr), are also elevated by CR throughout adulthood, although the global CR-specific expression profiles at young and older timepoints are highly divergent. At a previously unachieved resolution, our results demonstrate conserved activation of neuroprotective gene signatures and broad CR-suppression of age-dependent hippocampal CA1 region expression changes, indicating that CR functionally maintains a more youthful transcriptional state within hippocampal CA1 throughout aging. Hippocampal CA1 region mRNA profiles of younger- (5 months) and older-adult (15 months) mice on calorie-restricted (CR) and normal (AD) diets were generated by deep sequencing using Illumina HiSeq 2500.

Project description:Purpose: Leveraging genome-wide lineage-specific transcriptional profiling of human mammary luminal epithelial cells (LEPs) and myoepithelial cells (MEPs) to elucidate the molecular mechanisms underlying aging-associated breast cancer susceptibility. Methods: Human mammary luminal epithelial and myoepithelial cells were isolated from finite lifespan, non-immortalized human mammary epithelial cells (HMECs) derived from primary breast tissue of women across different age cohorts and breast cancer risk profiles. Transcriptional profiles of LEP and MEP cells were generated via RNA-sequencing performed on Illumina HiSeq 2500. RNA-Seq reads were trimmed using Trimmomatic software, and the processed reads were mapped back to the human genome (hg19) using TOPHAT2. Count matrices were generated using HTSeq. Results: Genome-wide loss of lineage fidelity is a hallmark of aging breast epithelia. Age-dependent differential expression occurred almost exclusively in luminal cells characterized by luminal epithelial cells of older women expressing markers normally expressed in myoepithelial cells. Luminal epithelial cells from histologically normal breast tissue from younger women who carry germline mutations in BRCA1, BRCA2, or PALB2 genes and who are considered to be clinically high risk for breast cancer also exhibited these hallmarks of accelerated aging. Furthermore, accelerated aging of these genetically high risk luminal epithelial cells could be predicted using a biological clock trained on gene expression and DNA methylation profiles of the luminal-specific ELF5 transcription factor. Conclusions: Our study shows that lineage-specific analysis is critical to understanding the molecular mechanisms underlying aging-associated cancer susceptibility. Our results suggest that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. Moreover, breast aging hallmarks identified in our study reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk.

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The biological age linked with oxidative estress modifies breast cancer aggressiveness

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