scholarly journals Epigenetic silencing of lncRNA MORT in 16 TCGA cancer types

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 211 ◽  
Author(s):  
Lukas Vrba ◽  
Bernard W. Futscher
Keyword(s):  
Dna Methylation ◽  
Mammary Epithelial Cells ◽  
Human Cancer ◽  
Large Fraction ◽  
Cell Types ◽  
Mammary Epithelial ◽  
The Cancer Genome Atlas ◽  
Human Mammary Epithelial ◽  
Cancer Types

We have previously described a hominid-specific long non-coding RNA, MORT (also known as ZNF667-AS1, Gene ID: 100128252), which is expressed in all normal cell types, but epigenetically silenced during cancer-associated immortalization of human mammary epithelial cells.  Initial analysis of The Cancer Genome Atlas (TCGA) showed that 15 of 17 cancer types, which represent the 10 most common cancers in women and men, display DNA methylation associated MORT silencing in a large fraction of their tumors.  In this study we analyzed MORT expression and DNA methylation state in the remaining 16 TCGA cancer types not previously reported.  Seven of the 16 cancer types showed DNA methylation linked MORT silencing in a large fraction of their tumors.  These are carcinomas (cervical cancer, and cancers of esophagus, stomach, and bile duct), and the non-epithelial tumors mesothelioma, sarcoma, and uterine carcinosarcoma.  Together with the findings from our previous report, MORT expression is silenced by aberrant DNA methylation in 22 of 33 of TCGA cancer types.  These 22 cancers include most carcinoma types, blood derived cancers and sarcomas.  In conclusion, results suggest that the MORT gene is one of the most common epigenetic aberrations seen in human cancer.  Coupled with the timing of MORT gene silencing during in vitro epithelial cell immortalization and its occurrence early in the temporal arc of human carcinogenesis, this provides strong circumstantial evidence for a tumor suppressor role for MORT.

Regulation of parathyroid hormone-related peptide production in normal human mammary epithelial cells in vitro

1994 ◽  
Vol 267 (3) ◽  
pp. C723-C730 ◽  
Author(s):  
M. Sebag ◽  
J. Henderson ◽  
D. Goltzman ◽  
R. Kremer
Keyword(s):  
Parathyroid Hormone ◽  
Growth Factor ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Igf I ◽  
Human Mammary Epithelial ◽  
Pthrp Expression ◽  
Normal Human ◽  
Parathyroid Hormone Related Peptide

We have examined the expression and production of parathyroid hormone-related peptide (PTHRP) in primary cultures of normal human mammary epithelial cells (HMEC) derived from nonlactating breast tissue. In response to growth factors such as insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor (EGF), immunoreactive PTHRP was released into conditioned medium, and PTHRP mRNA rapidly increased. In contrast, hydrocortisone and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibited these effects in a dose-dependent manner. Addition of prolactin (PRL) in the presence or absence of insulin, IGF-I, or EGF did not influence PTHRP production during the time course studied. To investigate whether these factors were acting at the transcriptional level, we performed nuclear run-on assays and demonstrated that IGF-I increased PTHRP gene transcription whereas hydrocortisone and 1,25(OH)2D3 inhibited this effect. These studies therefore demonstrate that IGF-I, EGF, 1,25(OH)2D3, and hydrocortisone modulate PTHRP expression in HMEC and that these effects occur in part at the level of gene transcription. Additionally, PRL, a known stimulator of PTHRP expression in vivo, has no effect in this in vitro model.

The role of native bovine α-lactalbumin in bovine mammary epithelial cell apoptosis and casein expression

2008 ◽  
Vol 75 (3) ◽  
pp. 319-325 ◽  
Author(s):  
Lisa G Riley ◽  
Peter C Wynn ◽  
Peter Williamson ◽  
Paul A Sheehy
Keyword(s):  
Epithelial Cells ◽  
Mrna Expression ◽  
Mammary Epithelial Cells ◽  
Cell Types ◽  
Mammary Epithelial ◽  
Major Influence ◽  
Expression Levels ◽  
Bovine Mammary Epithelial Cells ◽  
Epithelial Cell Apoptosis

Folding variants of α-lactalbumin (α-la) are known to induce cell death in a number of cell types, including mammary epithelial cells (MEC). The native conformation of α-la however has not been observed to exhibit this biological activity. Here we report that native bovine α-la reduced the viability of primary bovine mammary epithelial cells (BMEC) and induced caspase activity in mammospheres, which are alveolar-like structures formed by culturing primary BMEC on extracellular matrix in the presence of lactogenic hormones. These observations suggest a possible role for bovine α-la in involution and/or maintaining the luminal space in mammary alveoli during lactation. In addition, co-incubation of bovine α-la in an in-vitro mammosphere model resulted in decreased β-casein mRNA expression and increased αs1- and κ-casein mRNA expression. This differential effect on casein expression levels is unusual and raises the possibility of manipulating expression levels of individual caseins to alter dairy processing properties. Manipulation of α-la levels could be further investigated for its potential to enhance milk protein expression and/or improve lactational persistency by influencing the balance between proliferation and apoptosis of BMEC, which has a major influence on the milk-producing capacity of the mammary gland.

scholarly journals A Mathematical Model Quantifies Proliferation and Motility Effects of TGF-β on Cancer Cells

2009 ◽  
Vol 10 (1) ◽  
pp. 71-83 ◽  
Author(s):  
Shizhen Emily Wang ◽  
Peter Hinow ◽  
Nicole Bryce ◽  
Alissa M. Weaver ◽  
Lourdes Estrada ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Motility ◽  
Transforming Growth Factor ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Kolmogorov Equation ◽  
Human Mammary Epithelial

Transforming growth factor (TGF)-β is known to have properties of both a tumour suppressor and a tumour promoter. While it inhibits cell proliferation, it also increases cell motility and decreases cell–cell adhesion. Coupling mathematical modelling and experiments, we investigate the growth and motility of oncogene-expressing human mammary epithelial cells under exposure to TGF-β. We use a version of the well-known Fisher–Kolmogorov equation, and prescribe a procedure for its parametrisation. We quantify the simultaneous effects of TGF-β to increase the tendency of individual cells and cell clusters to move randomly and to decrease overall population growth. We demonstrate that in experiments with TGF-β treated cellsin vitro, TGF-β increases cell motility by a factor of 2 and decreases cell proliferation by a factor of 1/2 in comparison with untreated cells.

scholarly journals Distinct oncogenes drive distinct genome and epigenome alterations in human mammary epithelial cells

2018 ◽  
Author(s):  
Claire Fonti ◽  
Anne Saumet ◽  
Amanda Abi-Khalil ◽  
Béatrice Orsetti ◽  
William Jacot ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Cell Lineages ◽  
Human Mammary Epithelial Cells ◽  
Early Activation ◽  
Oncogenic Pathways ◽  
Human Mammary Epithelial

AbstractGene expression differences, combined with distinct patterns of genomic rearrangements and epigenetic modifications, have laid the bases of molecular classification of breast cancer. Different molecular subtypes are thought to originate from different cell lineages in the mammary gland, but the early activation of an oncogene could also play a role. It is, however, difficult to discriminate the respective inputs of oncogene activation or cell type of origin in the natural history of the tumor. In this work, we have designed an experimental strategy aiming at determining whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. We show that initial activation of CCNE1, WNT1 and RASv12, which activate distinct oncogenic pathways, in shp53 immortalized HMECs results in different and reproducible profiles of mRNA and miRNA expression, copy number alterations (CNA) and DNA methylation modifications. Noticeably, HMECs transformed by RAS bore very specific profiles of CNAs and DNA methylation, clearly distinct from those shown by CCNE1 and WNT1 transformed HMECs.Genes impacted by CNAs and CpG methylation in the RAS and the CCNE1/WNT1 clusters showed clear differences, illustrating the activation of distinct pathways. Our data show that early activation of distinct oncogenic pathways leads to active adaptive events resulting in specific sets of CNAs and DNA methylation changes. We, thus, propose that activation of different oncogenes could have a role in reshaping the genetic landscape of breast cancer subtypes.Author summaryGenetic and epigenetic changes are at the center of cancer development. Breast cancer molecular subtypes are defined on differences in genetic and epigenetic profiles and it is generally assumed these subtypes originate from different cell lineages in the mammary gland. We propose that founding oncogenic mutations could also have an impact. To address this question, we designed an experimental model, based on the ectopic expression of different oncogenes in human mammary epithelial cells (HMEC), and monitored genetic and DNA methylation changes occurring at different stages of cell transformation. We show that transformation of HMEC by distinct oncogenes resulted in clearly different and reproducible patterns of genetic and DNA methylation changes. Genes whose expression was modified by either CNAs or CpG methylation were consistent with the dominant pathways activated and reflected the phenotypes in the respective models. We propose that DNA methylation and CNA changes correspond to adaptive responses to the activation of the oncogenic pathways. Our data strongly suggest that early activation of distinct oncogenic insults will not only impinge on the phenotypic characteristics of the resulting tumors, but also have a strong impact on their genomic and epigenetic landscapes.

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