scholarly journals Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

2021 ◽  
Author(s):  
Rosalyn W. Sayaman ◽  
Masaru Miyano ◽  
Parijat Senapati ◽  
Sundus Shalabi ◽  
Arrianna Zirbes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Susceptibility ◽  
Epigenetic Changes ◽  
Cancer Initiation ◽  
Specific Manner ◽  
Age Dependent ◽  
Mammary Epithelia ◽  
Luminal Cells ◽  
Differential Variability

SummaryAging causes molecular changes that manifest as stereotypical phenotypes yet aging-associated diseases progress only in certain individuals. At lineage-specific resolution, we show how stereotyped and variant responses are integrated in mammary epithelia. Age-dependent directional changes in gene expression and DNA methylation (DNAm) occurred almost exclusively in luminal cells and implicated genome organizers SATB1 and CTCF. DNAm changes were robust indicators of aging luminal cells, and were either directly (anti-)correlated with expression changes or served as priming events for subsequent dysregulation, such as demethylation of ESR1-binding regions in DNAm-regulatory CXXC5 in older luminal cells and luminal-subtype cancers. Variance-driven changes in the transcriptome of both luminal and myoepithelial lineages further contributed to age-dependent loss of lineage fidelity. The pathways affected by transcriptomic and DNAm changes during aging are commonly linked with breast cancer, and together with the differential variability found across individuals, influence aging-associated cancer susceptibility in a subtype-specific manner.

scholarly journals Deep Proteome Profiling of Human Mammary Epithelia at Lineage and Age Resolution

2021 ◽  
Author(s):  
Stefan Hinz ◽  
Antigoni Manousopoulou ◽  
Masaru Miyano ◽  
Rosalyn W. Sayaman ◽  
Kristina Y. Aguilera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Total Proteins ◽  
Breast Epithelium ◽  
Network Analyses ◽  
Age Dependent ◽  
Dependent Protein ◽  
Mammary Epithelia ◽  
Luminal Cells

SUMMARYAge is the major risk factor in most carcinomas, yet little is known about how proteomes change with age in any human epithelium. We present comprehensive proteomes comprised of >9,000 total proteins, and >15,000 phosphopeptides, from normal primary human mammary epithelia at lineage resolution from ten women ranging in age from 19 to 68. Data were quality controlled, and results were biologically validated with cell-based assays. Age-dependent protein signatures were identified using differential expression analyses and weighted protein co-expression network analyses. Up-regulation of basal markers in luminal cells, including KRT14 and AXL, were a prominent consequence of aging. PEAK1 was identified as an age-dependent signaling kinase in luminal cells, which revealed a potential age-dependent vulnerability for targeted ablation. Correlation analyses between transcriptome and proteome revealed age-associated loss of proteostasis regulation. Protein expression and phosphorylation changes in the aging breast epithelium identify potential therapeutic targets for reducing breast cancer susceptibility.

scholarly journals Circadian Gene Polymorphisms Associated with Breast Cancer Susceptibility

2019 ◽  
Vol 20 (22) ◽  
pp. 5704
Author(s):  
Monika Lesicka ◽  
Ewa Jabłońska ◽  
Edyta Wieczorek ◽  
Beata Pepłońska ◽  
Jolanta Gromadzińska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Genetic Model ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
High Resolution Melt ◽  
Circadian Genes ◽  
Increased Risk ◽  
Dominant Genetic Model ◽  
Variant Genotype

Breast cancer (BC) is a major problem for civilization, manifested by continuously increasing morbidity and mortality among women worldwide. Core circadian genes may play an important role in cancer development and progression. To evaluate the effects of single nucleotide polymorphism (SNP) in circadian genes in BC risk, 16 functional SNPs were genotyped in 321 BC patients and 364 healthy women using the TaqMan fluorescence-labelled probes or High-Resolution Melt Curve technique in the Real-Time PCR system. The selected SNPs were analyzed for the risk of BC, progression, and the influence on gene expression in BC tissue pairs to demonstrate the functionality of genetic variants. The study showed a relationship between an increased BC risk under the dominant genetic model of CRY2 rs10838524, PER2 rs934945, and recessive genetic model of PER1 rs2735611. A protective effect of BMAL1 rs2279287 was observed among carriers with at least one variant allele. Moreover, we found an increased risk of estrogen-/progesterone-positive tumors under the dominant genetic model of PER2 rs934945 and estrogen negative tumors under the variant genotype of CRY2 rs10838524, PER1 rs2735611. We demonstrated significantly altered gene expression of BMAL1, CRY2, PER1, PER2, PER3 according to particular genotypes in the BC tissue pairs. Our findings support the hypothesized role of circadian genes in breast carcinogenesis and indicate probable biomarkers for breast cancer susceptibility.

scholarly journals Exonic sequencing and MLH3 gene expression analysis of breast cancer patients

2021 ◽  
Vol 67 (3) ◽  
pp. 35-43
Author(s):  
Rozhgar A. Khailany ◽  
Mehmet Ozaslan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Exome Sequencing ◽  
Cancer Patients ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Breast Cancer Susceptibility ◽  
Breast Cancer Patients ◽  
Cancer Susceptibility Genes ◽  
Mlh3 Gene

Breast cancer is the most common cancer in women worldwide. Detection of breast cancer susceptibility genes is an important issue. Also, MLH3 is a DNA mismatch repair gene and mutation in this gene is harmful in different cancers. This study aimed to use exome sequencing to uncover previously undetected breast cancer-predisposing variants. Also, we investigated the MLH3 gene expression of breast cancer patients which can be a breast cancer susceptibility gene. A total of 80 samples including 40 paired normal and cancer tissue samples were collected at Zheen International Hospital, Erbil, Iraq. Exome sequencing was used to identify mutations. Different in silico tools were used to predict the effect of mutation on the structural features or protein function. Real-time PCR was used for assessing the expression of MLH3 in breast cancer patients. We identified 26 variants in breast cancer patients, 22 inherited variants were found in MLH3, CHECK2, BRCA1, BRCA2, BLM, TP53, MSH6, NBN and PTEN genes and 4 somatic variants were found in PALB2, RAD50 and RBM10 genes. It was found that the expression of the MLH3 gene in tumor samples was significantly down-regulated compared with normal tissues. Statistically, high significance was found. The decreased expression of MLH3 was significant in all ranges of ages and all breast cancer types. Also, the expression of MLH3 decreased significantly in patients with breast cancer grades of II and III. In conclusion, MLH3 can be used as a susceptibility gene especially in grades II and III of breast cancer.

Epigenetic control of breast cancer susceptibility.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1560-1560
Author(s):  
Natascia Marino ◽  
Rana German ◽  
Nakshatri Harikrishna ◽  
Ram Podicheti ◽  
Ashley Vode ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Methylation ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Breast Tissue ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Average Risk ◽  
Coding Regions

1560 Background: Epigenetic mechanisms such as DNA methylation are important regulators of gene expression and are frequently dysregulated early in breast carcinogenesis. The relationship between DNA methylation aberrations in normal breast tissue and breast cancer risk remains unclear. Methods: Disease-free breast tissue cores donated by 71 high-risk (Tyrer-Cuzick lifetime risk ≥20%) and 79 average-risk women were obtained from the Komen Tissue Bank and processed for whole methylome (Diagenode's MethylCap Library and single-end 75-bp sequencing on Illumina Nextseq) and whole transcriptome (Illumina Nextseq) profiling. Reads from RNA-seq data were aligned to the human genome reference, GRCh38.p12 using STAR v.2.5.2b and tested for differential gene expression using DESeq2 ver. 1.24.0. For DNA methylation data, difference of variation in deduplicated read coverage among 250-bp fixed sized bins spanning CpG islands between high- and average-risk libraries was computed as z-ratios to identify differentially methylated regions. Pathway analysis was performed using IPA v06_01. Results: We identified 1355 CpGs that were differentially methylated between high- and average-risk breast tissues (ΔZ > 0.5, FDR < 0.05). Hypomethylated CpGs were overrepresented in high-risk tissue and were found predominantly (68%) in non-coding regions. Hypermethylated CpG sites were found equally in the gene body and non-coding regions. Transcriptomic analysis identified 112 differentially expressed genes (fold change≥2, FDR < 0.05), involved in chemokines signaling, metabolism and estrogen biosynthesis. Among those, FAM83A (logfc = 2.3, FDR = 0.004) was previously described as epigenetically dysregulated in multiple cancers and transforms breast epithelial cell in vitro. Methylation-expression correlations revealed 11 epigenetically regulated genes including cellular transformation-associated BMPR1B. Two hypomethylated/upregulated long non-coding RNAs were also identified in high-risk breasts. Conclusions: This is the first gene expression/DNA methylation analysis of normal breasts from women at either high or average risk of breast cancer. Our discovery of epigenetically regulated genes associated with breast cancer risk provides an opportunity to mechanistically dissect breast cancer susceptibility and risk-associated molecular alterations. Unlike the current focus of identifying germline mutations or single nucleotide polymorphisms responsible for higher risk, our studies reveal an epigenetic mechanism, which is not discernable through simple genomic sequencing.

scholarly journals Breast Cancer beyond the Age of Mutation

Gerontology ◽  
2015 ◽  
Vol 62 (4) ◽  
pp. 434-442 ◽  
Author(s):  
Mark A. LaBarge ◽  
E. Lorena Mora-Blanco ◽  
Susan Samson ◽  
Masaru Miyano
Keyword(s):  
Breast Cancer ◽  
Cancer Incidence ◽  
Breast Tissue ◽  
Breast Cancer Incidence ◽  
Epigenetic Changes ◽  
Breast Cancers ◽  
Age Related ◽  
Age Dependent ◽  
Tissue Changes ◽  
Cellular Phenotypes

Age is the greatest risk factor for breast cancer, but the reasons underlying this association are unclear. While there is undeniably a genetic component to all cancers, the accumulation of mutations with age is insufficient to explain the age-dependent increase in breast cancer incidence. In this viewpoint, we propose a multilevel framework to better understand the respective roles played by somatic mutation, microenvironment, and epigenetics making women more susceptible to breast cancer with age. The process of aging is associated with gradual breast tissue changes that not only corrupt the tumor-suppressive activity of normal tissue but also impose age-specific epigenetic changes that alter gene expression, thus reinforcing cellular phenotypes that are associated with a continuum of age-related tissue microenvironments. The evidence discussed here suggests that while the riddle of whether epigenetics drives microenvironmental changes, or whether changes in the microenvironment alter heritable cellular memory has not been solved, a path has been cleared enabling functional analysis leading to the prediction of key nodes in the network that link the microenvironment with the epigenome. The hypothesis that the accumulation of somatic mutations with age drives the age-related increase in breast cancer incidence, if correct, has a somewhat nihilistic conclusion, namely that cancers will be impossible to avoid. Alternatively, if microenvironment-driven epigenetic changes are the key to explaining susceptibility to age-related breast cancers, then there is hope that primary prevention is possible because epigenomes are relatively malleable.

scholarly journals Haplotypes associated to gene expression in breast cancer: can they lead us to the susceptibility markers?

2018 ◽  
Author(s):  
Hege Edvardsen ◽  
Bettina Kulle ◽  
Anya Tsalenko ◽  
Grethe Irene Grenaker Alnӕs ◽  
Fredrik Ekeberg Johansen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Patients ◽  
Haplotype Analysis ◽  
Cancer Susceptibility ◽  
Expression Patterns ◽  
Breast Cancer Patients ◽  
Haplotype Distribution ◽  
Significant Difference ◽  
History Of

AbstractWe have undertaken a systematic haplotype analysis of the positional type of biclusters analysing samples collected from 164 breast cancer patients and 86 women with no known history of breast cancer. We present here the haplotypes and LD patterns in more than 80 genes distributed across all chromosomes and how they differ between cases and controls. We aim by this to 1) identify genes with different haplotype distribution or LD patterns between breast cancer patients and controls and 2) to evaluate the intratumoral mRNA expression patterns in breast cancer associated particularly to the cancer susceptibility haplotypes. A significant difference in haplotype distribution between cases and controls was observed for a total of 35 genes including ABCC1, AKT2, NFKB1, TGFBR2 and XRCC4. In addition we see a negative correlation between LD patterns in cases and controls for neighboring markers in 8 genes such as CDKN1A, EPHX1 and XRCC1.

scholarly journals MicroRNA Regulation of Epigenetic Modifiers in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 897 ◽  
Author(s):  
Brock Humphries ◽  
Zhishan Wang ◽  
Chengfeng Yang
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Microrna Regulation ◽  
Epigenetic Biomarkers ◽  
Cancer Initiation ◽  
Research Findings ◽  
Aberrant Dna Methylation ◽  
Histone Modification Patterns

Epigenetics refers to the heritable changes in gene expression without a change in the DNA sequence itself. Two of these major changes include aberrant DNA methylation as well as changes to histone modification patterns. Alterations to the epigenome can drive expression of oncogenes and suppression of tumor suppressors, resulting in tumorigenesis and cancer progression. In addition to modifications of the epigenome, microRNA (miRNA) dysregulation is also a hallmark for cancer initiation and metastasis. Advances in our understanding of cancer biology demonstrate that alterations in the epigenome are not only a major cause of miRNA dysregulation in cancer, but that miRNAs themselves also indirectly drive these DNA and histone modifications. More explicitly, recent work has shown that miRNAs can regulate chromatin structure and gene expression by directly targeting key enzymes involved in these processes. This review aims to summarize these research findings specifically in the context of breast cancer. This review also discusses miRNAs as epigenetic biomarkers and as therapeutics, and presents a comprehensive summary of currently validated epigenetic targets in breast cancer.

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