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 DNA Methylation and Breast Cancer Risk: An Epigenome-Wide Study of Normal Breast Tissue and Blood

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3088 ◽  
Author(s):  
Kaoutar Ennour-Idrissi ◽  
Dzevka Dragic ◽  
Elissar Issa ◽  
Annick Michaud ◽  
Sue-Ling Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Breast Epithelium ◽  
Normal Breast Epithelium ◽  
Differentially Methylated Genes

Differential DNA methylation is a potential marker of breast cancer risk. Few studies have investigated DNA methylation changes in normal breast tissue and were largely confounded by cancer field effects. To detect methylation changes in normal breast epithelium that are causally associated with breast cancer occurrence, we used a nested case–control study design based on a prospective cohort of patients diagnosed with a primary invasive hormone receptor-positive breast cancer. Twenty patients diagnosed with a contralateral breast cancer (CBC) were matched (1:1) with 20 patients who did not develop a CBC on relevant risk factors. Differentially methylated Cytosine-phosphate-Guanines (CpGs) and regions in normal breast epithelium were identified using an epigenome-wide DNA methylation assay and robust linear regressions. Analyses were replicated in two independent sets of normal breast tissue and blood. We identified 7315 CpGs (FDR < 0.05), 52 passing strict Bonferroni correction (p < 1.22 × 10−7) and 43 mapping to known genes involved in metabolic diseases with significant enrichment (p < 0.01) of pathways involving fatty acids metabolic processes. Four differentially methylated genes were detected in both site-specific and regions analyses (LHX2, TFAP2B, JAKMIP1, SEPT9), and three genes overlapped all three datasets (POM121L2, KCNQ1, CLEC4C). Once validated, the seven differentially methylated genes distinguishing women who developed and who did not develop a sporadic breast cancer could be used to enhance breast cancer risk-stratification, and allow implementation of targeted screening and preventive strategies that would ultimately improve breast cancer prognosis.

scholarly journals Androgen receptor expression in normal breast tissue and subsequent breast cancer risk

2018 ◽  
Vol 4 (1) ◽  
Author(s):  
Kevin H. Kensler ◽  
Francisco Beca ◽  
Gabrielle M. Baker ◽  
Yujing J. Heng ◽  
Andrew H. Beck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Receptor Expression ◽  
Androgen Receptor Expression

scholarly journals Evidence of Accelerated Epigenetic Aging of Breast Tissues In Patients With Breast Cancer Is Driven By CpGs Associated With Polycomb Related Genes

2021 ◽  
Author(s):  
Mariya Rozenblit ◽  
Erin Hofstatter ◽  
Zuyun Liu ◽  
Tess O'Meara ◽  
Anna Maria Storniolo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Peripheral Blood ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

Abstract Purpose: Age is one of the strongest risk factors for the development of breast cancer, however the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods: Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results: The Levine (p=0.0037) and Yang clocks (p=0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p=0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions: Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb related genes can be used to assess the risk of developing breast cancer among unaffected individuals.

Expression of miR-18a and miR-210 in Normal Breast Tissue as Candidate Biomarkers of Breast Cancer Risk

2016 ◽  
Vol 10 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Ali Shidfar ◽  
Fabricio F. Costa ◽  
Denise Scholtens ◽  
Jared M. Bischof ◽  
Megan E. Sullivan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast

The role of low keV virtual monochromatic imaging in increasing the conspicuity of primary breast cancer in dual-energy spectral thoracic CT examination for staging purposes

2019 ◽  
Vol 61 (2) ◽  
pp. 168-174 ◽  
Author(s):  
Yavuz Metin ◽  
Nurgül Orhan Metin ◽  
Oğuzhan Özdemir ◽  
Filiz Taşçı ◽  
Sibel Kul
Keyword(s):  
Breast Cancer ◽  
Primary Breast Cancer ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Energy Levels ◽  
Iodine Content ◽  
Pectoral Muscle ◽  
Dual Energy ◽  
Normal Breast

Background The additive value of dual-energy spectral computerized tomography (DESCT) in breast cancer imaging is still unknown. Purpose To investigate the role of DESCT in improving the conspicuity of primary breast cancer. Material and Methods Twenty-nine patients who were histopathologically diagnosed with breast cancer and underwent DESCT for staging of lung metastasis were evaluated retrospectively. The visual conspicuity of breast cancer was scored by two readers separately in reconstructed virtual monochromatic images obtained at 40, 60, 80, and 100 keV. A circular region of interest slightly smaller than the maximum contrasted portion of the primary breast cancer was manually placed. Iodine enhancement (HU) and iodine content (mg/mL) values of tumor, normal breast tissue and pectoral muscle, and contrast-to-noise values of images at four different energy levels were calculated. Results The lesion conspicuity score peaked at 40-keV series for both readers and was significantly higher than those at other energy levels (all P < 0.001). Lesion iodine enhancement was highest at 40-keV virtual monochromatic image reconstructions ( P < 0.001). The iodine content was significantly higher in tumor than normal breast tissue, and pectoral muscle ( P < 0.001). The highest contrast-to-noise value was obtained at 60 keV (4.0 ± 2.5), followed by 40 keV (3.9 ± 2.2), without a significant difference ( P = 0.33). Conclusion The conspicuity of primary breast cancer was significantly higher in low keV virtual monochromatic images obtained by DESCT. This gives us hope that DESCT may play an effective role in detecting incidental breast lesions. It also raises the question of whether quantitative values obtained by DESCT can be used for characterization of primary breast lesion.

scholarly journals Progesterone and Breast Cancer

2019 ◽  
Vol 41 (2) ◽  
pp. 320-344 ◽  
Author(s):  
Britton Trabert ◽  
Mark E Sherman ◽  
Nagarajan Kannan ◽  
Frank Z Stanczyk
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Normal Breast ◽  
Cancer Etiology ◽  
Progesterone Metabolites ◽  
Breast Physiology ◽  
Independent Effects ◽  
The Individual

Abstract Synthetic progestogens (progestins) have been linked to increased breast cancer risk; however, the role of endogenous progesterone in breast physiology and carcinogenesis is less clearly defined. Mechanistic studies using cell culture, tissue culture, and preclinical models implicate progesterone in breast carcinogenesis. In contrast, limited epidemiologic data generally do not show an association of circulating progesterone levels with risk, and it is unclear whether this reflects methodologic limitations or a truly null relationship. Challenges related to defining the role of progesterone in breast physiology and neoplasia include: complex interactions with estrogens and other hormones (eg, androgens, prolactin, etc.), accounting for timing of blood collections for hormone measurements among cycling women, and limitations of assays to measure progesterone metabolites in blood and progesterone receptor isotypes (PRs) in tissues. Separating the individual effects of estrogens and progesterone is further complicated by the partial dependence of PR transcription on estrogen receptor (ER)α-mediated transcriptional events; indeed, interpreting the integrated interaction of the hormones may be more essential than isolating independent effects. Further, many of the actions of both estrogens and progesterone, particularly in “normal” breast tissues, are driven by paracrine mechanisms in which ligand binding to receptor-positive cells evokes secretion of factors that influence cell division of neighboring receptor-negative cells. Accordingly, blood and tissue levels may differ, and the latter are challenging to measure. Given conflicting data related to the potential role of progesterone in breast cancer etiology and interest in blocking progesterone action to prevent or treat breast cancer, we provide a review of the evidence that links progesterone to breast cancer risk and suggest future directions for filling current gaps in our knowledge.

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