JMJD6 induces HOTAIR, an oncogenic lincRNA, by physically interacting with its proximal promoter

2018 ◽  
Vol 475 (1) ◽  
pp. 355-371 ◽  
Author(s):  
Antara Biswas ◽  
Abhijith Shettar ◽  
Geetashree Mukherjee ◽  
Paturu Kondaiah ◽  
Kartiki V. Desai
Keyword(s):  
Breast Cancer ◽  
Breast Tissue ◽  
Normal Breast ◽  
Proximal Promoter ◽  
Poor Survival ◽  
Hek 293 ◽  
293 Cells ◽  
Arginine Demethylase ◽  
Promoter Mutant ◽  
Mcf 7

Using microarray analysis, we found that HOX transcript antisense intergenic RNA (HOTAIR) is up-regulated by Jumonji domain containing-6 (JMJD6), a bifunctional lysyl hydroxylase and arginine demethylase. In breast cancer, both JMJD6 and HOTAIR RNAs increase tumor growth and associate with poor prognosis but no molecular relationship between them is known. We show that overexpression of JMJD6 increased HOTAIR expression and JMJD6 siRNAs suppressed it in ER+ MCF-7, triple negative MDA-MB-231 and non-breast cancer HEK 293 cells. Therefore, JMJD6 regulates HOTAIR independent of ER status. Using various deletion constructs spanning (−1874 to +50) of the HOTAIR promoter, we identified pHP216 (−216 to +50 bp) as the smallest construct that retained maximal JMJD6 responsiveness. In ChIP assays, JMJD6 bound this region suggesting that JMJD6 may be directly recruited to the HOTAIR promoter. Mutant JMJD6H187A that is devoid of enzymatic activity could bind this site but failed to induce transcription. ChIP and electromobility shift assays identified a JMJD6 interaction region from (−123 to −103 bp) within the HOTAIR promoter. In tumor samples but not normal breast tissue, the expression of JMJD6 linearly correlated with HOTAIR suggesting that JMJD6-mediated up-regulation may occur specifically in tumors. Further, concurrent high expression of both genes correlated with poor survival when individual expression of either gene showed no significant association in TCGA datasets. We propose that high JMJD6 expression may achieve higher levels of HOTAIR in breast tumors. Further, since high levels of HOTAIR promote metastasis and death, blocking JMJD6 may be useful in preventing such events.

scholarly journals PAPOLA contributes to Cyclin D1 mRNA alternative polyadenylation and promotes breast cancer cells proliferation

2021 ◽  
pp. jcs.252304
Author(s):  
Chrysoula Komini ◽  
Irini Theohari ◽  
Andromachi Lambrianidou ◽  
Lydia Nakopoulou ◽  
Theoni Trangas
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Alternative Polyadenylation ◽  
Hek 293 ◽  
Protein Levels ◽  
293 Cells ◽  
Candidate Target ◽  
Mcf 7

Poly(A) polymerases add the poly(A) tail at the 3’ end of nearly all eukaryotic mRNA, are associated with proliferation and cancer. To elucidate the role of the most studied mammalian poly(A) polymerase α (PAPOLA) in cancer, we assessed its expression in 221 breast cancer samples and found it to correlate strongly with the aggressive triple-negative subtype. Silencing PAPOLA in MCF-7 and MDA-MB-231 breast cancer cells reduced proliferation and anchorage-independent growth by decreasing steady-state CCND1 mRNA and protein levels. Whereas the length of the CCND1 mRNA poly(A) tail was not affected, its 3' untranslated region (3'UTR) lengthened. Overexpressing PAPOLA caused CCND1 mRNA 3'UTR shortening with a concomitant increase in the corresponding transcript and protein, resulting in growth arrest in MCF-7 cells and DNA damage in HEK-293 cells, whereas in the P53 mutant MDA-MB-231 promoted proliferation.Our data suggest PAPOLA as a possible candidate target for the control of tumor growth, mostly relevant to triple-negative tumors, a group characterized by its overexpression and lacking alternative targeted therapies.

scholarly journals The Expression Pattern of Epidermal Differentiation Marker Keratin 10 in the Normal Human Breast and Breast Cancer Cells

2020 ◽  
Vol 68 (8) ◽  
pp. 561-570
Author(s):  
Jiyoung Kim ◽  
René Villadsen
Keyword(s):  
Breast Cancer ◽  
Expression Pattern ◽  
Breast Tissue ◽  
Normal Breast ◽  
Epidermal Differentiation ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Normal Human Breast ◽  
Differentiation Marker ◽  
Breast Gland

Cells of the human breast gland express an array of keratins, of which some are used for characterizing both normal and neoplastic breast tissue. However, the expression pattern of certain keratins has yet to be detailed. Here, the expression of a differentiation marker of epidermal epithelium, keratin 10 (K10), was investigated in the human breast gland. While in normal breast tissue generally less than 1% of luminal epithelial cells expressed K10, in women >30 years of age glandular structures with K10-positive (K10pos) cells were found at higher frequency than in younger women. K10pos cells belong to a mature luminal compartment as they were negative for cKIT, positive for Ks20.8, and mostly non-cycling. In breast cancer, around 16% of primary breast carcinomas tested were positive for K10 by immunohistochemistry. Interestingly, K10pos tumor cells generally exhibit features of differentiation similar to their normal counterparts. Although this suggests that K10 is a marker of tumor differentiation, data based on gene expression analysis imply that high levels of K10 dictate a worse outcome for breast cancer patients. These findings can form the basis of future studies that should unravel which role K10 may play as a marker of breast cancer:

scholarly journals Accelerated aging in normal breast tissue of women with breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Shoghag Panjarian ◽  
Jozef Madzo ◽  
Kelsey Keith ◽  
Carolyn M. Slater ◽  
Carmen Sapienza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Anomaly Detection ◽  
Breast Tissue ◽  
Preventive Intervention ◽  
Normal Breast Tissue ◽  
Accelerated Aging ◽  
Normal Breast ◽  
Age Related ◽  
Unsupervised Anomaly Detection

Abstract Background DNA methylation alterations have similar patterns in normal aging tissue and in cancer. In this study, we investigated breast tissue-specific age-related DNA methylation alterations and used those methylation sites to identify individuals with outlier phenotypes. Outlier phenotype is identified by unsupervised anomaly detection algorithms and is defined by individuals who have normal tissue age-dependent DNA methylation levels that vary dramatically from the population mean. Methods We generated whole-genome DNA methylation profiles (GSE160233) on purified epithelial cells and used publicly available Infinium HumanMethylation 450K array datasets (TCGA, GSE88883, GSE69914, GSE101961, and GSE74214) for discovery and validation. Results We found that hypermethylation in normal breast tissue is the best predictor of hypermethylation in cancer. Using unsupervised anomaly detection approaches, we found that about 10% of the individuals (39/427) were outliers for DNA methylation from 6 DNA methylation datasets. We also found that there were significantly more outlier samples in normal-adjacent to cancer (24/139, 17.3%) than in normal samples (15/228, 5.2%). Additionally, we found significant differences between the predicted ages based on DNA methylation and the chronological ages among outliers and not-outliers. Additionally, we found that accelerated outliers (older predicted age) were more frequent in normal-adjacent to cancer (14/17, 82%) compared to normal samples from individuals without cancer (3/17, 18%). Furthermore, in matched samples, we found that the epigenome of the outliers in the pre-malignant tissue was as severely altered as in cancer. Conclusions A subset of patients with breast cancer has severely altered epigenomes which are characterized by accelerated aging in their normal-appearing tissue. In the future, these DNA methylation sites should be studied further such as in cell-free DNA to determine their potential use as biomarkers for early detection of malignant transformation and preventive intervention in breast cancer.

scholarly journals Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

2020 ◽  
Author(s):  
Toshiaki Akahane ◽  
Naoki Kanomata ◽  
Oi Harada ◽  
Tetsumasa Yamashita ◽  
Junichi Kurebayashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Primary Breast Cancer ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Metastatic Breast ◽  
Normal Breast ◽  
Human Breast ◽  
Metastatic Lesions ◽  
Generation Sequencing

Abstract Background: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions.Methods: Triplet samples of genomic DNA were extracted from each patient’s normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis.Results: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions.Conclusions: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

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.

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.

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