scholarly journals Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer

2016 ◽  
Vol 10 ◽  
pp. BCBCR.S39384 ◽  
Author(s):  
David N. Danforth
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
High Risk ◽  
Breast Tissue ◽  
Sporadic Breast Cancer ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Breast Carcinogenesis ◽  
Molecular Changes ◽  
Breast Tissues

Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women.

Abstract 71: Relationship of mammographic density and gene expression analysis of normal breast tissue surrounding breast cancer.

2012 ◽  
Vol 21 (11 Supplement) ◽  
pp. 71-71
Author(s):  
Xuezheng Sun ◽  
Gretchen L. Gierach ◽  
Rupninder Sandhu ◽  
Tyisha Williams ◽  
Norman Boyd ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Mammographic Density ◽  
Expression Analysis ◽  
Breast Tissue ◽  
Gene Expression Analysis ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Relationship Of

scholarly journals Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

2015 ◽  
Vol 25 (10) ◽  
pp. 1521-1535 ◽  
Author(s):  
Lars A. Forsberg ◽  
Chiara Rasi ◽  
Gyula Pekar ◽  
Hanna Davies ◽  
Arkadiusz Piotrowski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Tissue ◽  
Sporadic Breast Cancer ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Genetic Aberrations

scholarly journals Rho GTPase transcriptional activity and breast cancer risk: A Mendelian randomization analysis

2020 ◽  
Author(s):  
Nabila Kazmi ◽  
Tim Robinson ◽  
Jie Zheng ◽  
Siddhartha Kar ◽  
Richard M Martin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Rho Gtpases ◽  
Breast Tissue ◽  
Rho Gtpase ◽  
Normal Breast Tissue ◽  
Normal Breast

AbstractBackgroundRho GTPases are a family of 20 intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. Rho GTPases are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR).MethodsMR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER-) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding.ResultsWe identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI): 1.03, 1.09; P=5.65×10-5) and OR 1.22 (95% CI: 1.11, 1.35; P=5.22×10−5) in normal breast tissue and blood respectively). The direction of association was consistent for ER- breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was inversely associated with overall and ER+ breast cancer risk. The evidence from colocalization analyses strongly supported the MR results particularly for RHOD.ConclusionsOur study suggests a potential causal role of increased RHOD gene expression, and a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.

scholarly journals Aberrant epigenetic and transcriptional events associated with breast cancer risk

2021 ◽  
Author(s):  
Natascia Marino ◽  
Rana German ◽  
Ram Podicheti ◽  
Douglas B. Rush ◽  
Pam Rockey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Epithelial Cells ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Normal Breast ◽  
Breast Tissues

ABSTRACTBackgroundGenome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N=146, median age=39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina’s HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation.ResultsTranscriptomic analysis identified 69 differentially expressed genes between women at either high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR<0.05 and fold change≥2. The majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR<0.01) and primary epithelial cells (p<0.05) from high-risk breasts. Moreover, 1698 DNA methylation aberrations were identified in high-risk breast tissues (FDR<0.05), partially overlapped with cancer-related signatures and correlated with transcriptional changes (p<0.05, r≤0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified.ConclusionsNormal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.

Immunomodulatory pathways in both breast cancer and placental tissues: Insights from a unique clinical and genomic case report.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 13-13
Author(s):  
Miguel Hernandez Bronchud
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Lymph Node ◽  
Immune Tolerance ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Tissue Type ◽  
Immune Gene ◽  
Axillary Lymph

13 Background: some cancers might partially ectopically express intrinsic immune escape gene programs naturally developed during mammalian evolution to allow for materno-fetal immune tolerance. Methods: Genomic analysis (Nanostring Inc, Seattle, WA, USA) was carried out in primary breast cancer with metastatic homolateral axillary lymph nodes as well as placenta tissue (both uterine decidual tissue and term placenta tissue) from a pregnant woman (same patient). Gene expression profiling of paired non-self and self tissues (i.e. placenta/uterus; breast cancer/normal breast tissue; metastatic lymphnode/normal lymphnode tissue) was performed using the PanCancer Immune gene panel, a 770 Nanostring gene expression panel. Results: Our findings reveal overlapping in specific immune gene expression in placenta and cancer tissue, suggesting that these genes might play an important role in maintaining immune tolerance both physiologically (placenta) and pathologically ( cancer). Placenta and uterus, breast tissues (tumor and normal) and lymph node tissues (tumor and normal) formed their own RNA transcription cluster, suggesting that tissue specific gene expression patterns were well preserved during experimental procedures . We analyzed differential expression within each tissue type (i.e. matching for the analysis placenta with uterus, breast cancer with normal breast tissue and node positive with node negative tissue). Among the 583 genes analyzed, 103 genes were upregulated > 1.5 fold in placenta versus uterus, while 258 genes were downregulated at least 1.5 fold. Using the same cut-off, 258 genes were upregulated and 44 genes downregulated in breast tumor versus normal breast tissue, and 178 genes were upregulated while 146 genes downregulated in tumor bearing lymph node versus non-involved lymph node. Conclusions: A variety of complex immune regulation mechanisms seem to be shared by both placental tissues and cancer.

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