scholarly journals Interleukin-6–mediated epigenetic control of the VEGFR2 gene induces disorganized angiogenesis in human breast tumors

2020 ◽  
Vol 295 (34) ◽  
pp. 12086-12098
Author(s):  
Mangala Hegde ◽  
Kanive Parashiva Guruprasad ◽  
Lingadakai Ramachandra ◽  
Kapaettu Satyamoorthy ◽  
Manjunath B. Joshi
Keyword(s):  
T Cells ◽  
Interleukin 6 ◽  
Breast Tumor ◽  
Dna Methyltransferase ◽  
Growth Factor Receptor ◽  
Breast Tumors ◽  
Dominant Negative ◽  
Human Breast ◽  
Paracrine Factors ◽  
Altered Expression

Disorganized vessels in the tumor vasculature lead to impaired perfusion, resulting in reduced accessibility to immune cells and chemotherapeutic drugs. In the breast tumor–stroma interplay, paracrine factors such as interleukin-6 (IL-6) often facilitate disordered angiogenesis. We show here that epigenetic mechanisms regulate the crosstalk between IL-6 and vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways in myoepithelial (CD10+) and endothelial (CD31+, CD105+, CD146+, and CD133−) cells isolated from malignant and nonmalignant tissues of clinically characterized human breast tumors. Tumor endothelial (Endo-T) cells in 3D cultures exhibited higher VEGFR2 expression levels, accelerated migration, invasion, and disorganized sprout formation in response to elevated IL-6 levels secreted by tumor myoepithelial (Epi-T) cells. Constitutively, compared with normal endothelial (Endo-N) cells, Endo-T cells differentially expressed DNA methyltransferase isoforms and had increased levels of IL-6 signaling intermediates such as IL-6R and signal transducer and activator of transcription 3 (STAT3). Upon IL-6 treatment, Endo-N and Endo-T cells displayed altered expression of the DNA methyltransferase 1 (DNMT1) isoform. Mechanistic studies revealed that IL-6 induced proteasomal degradation of DNMT1, but not of DNMT3A and DNMT3B and subsequently led to promoter hypomethylation and expression/activation of VEGFR2. IL-6–induced VEGFR2 up-regulation was inhibited by overexpression of DNMT1. Transfection of a dominant-negative STAT3 mutant, but not of STAT1, abrogated VEGFR2 expression. Our results indicate that in the breast tumor microenvironment, IL-6 secreted from myoepithelial cells influences DNMT1 stability, induces the expression of VEGFR2 in endothelial cells via a promoter methylation–dependent mechanism, and leads to disordered angiogenesis.

scholarly journals Expression of Estrogen Receptor-β in Human Breast Tumors

1997 ◽  
Vol 82 (7) ◽  
pp. 2371-2374 ◽  
Author(s):  
Helmut Dotzlaw ◽  
Etienne Leygue ◽  
Peter H. Watson ◽  
Leigh C. Murphy
Keyword(s):  
Estrogen Receptor ◽  
Cell Lines ◽  
Breast Tumor ◽  
Breast Tumors ◽  
Breast Epithelial Cell ◽  
Pcr Analysis ◽  
Human Testis ◽  
Human Breast ◽  
Tumor Biopsy ◽  
Pcr Product

The expression of a recently described novel estrogen receptor, ER-β, was detected in several human breast tumor biopsy samples and several human breast epithelial cell lines using reverse transcription and polymerase chain reaction (RT-PCR) analysis. Cloning and sequencing of the PCR product from a breast tumor confirmed the identity of the sequence with that of the ER-β mRNA previously reported in human testis. The expression of ER-β was not correlated with that of ER-α, and both ER-α positive and ER-α negative cell lines expressed ER-β mRNA. However, some breast tumors and some cell lines coexpress ER-β and ER-α mRNA. Our data support a possible role for ER-β in human breast cancer.

scholarly journals Human breast tumor-infiltrating CD8+ T cells retain polyfunctionality despite PD-1 expression

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Colt A. Egelston ◽  
Christian Avalos ◽  
Travis Y. Tu ◽  
Diana L. Simons ◽  
Grecia Jimenez ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Breast Tumor ◽  
Human Breast ◽  
Human Breast Tumor

IR spectroscopy and IR microscopy of human breast tumors, xenografted breast tumors, and breast tumor cell lines

1998 ◽  
Author(s):  
Heinz Fabian ◽  
Ralf Wessel ◽  
Michael Jackson ◽  
Arnfried Schwartz ◽  
Peter Lasch ◽  
...  
Keyword(s):  
Ir Spectroscopy ◽  
Tumor Cell ◽  
Cell Lines ◽  
Breast Tumor ◽  
Breast Tumors ◽  
Tumor Cell Lines ◽  
Human Breast ◽  
Breast Tumor Cell ◽  
Ir Microscopy

A comparative infrared spectroscopic study of human breast tumors and breast tumor cell xenografts

1995 ◽  
Vol 1 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Heinz Fabian ◽  
Michael Jackson ◽  
Leigh Murphy ◽  
Peter H. Watson ◽  
Iduna Fichtner ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Spectroscopic Study ◽  
Breast Tumor ◽  
Breast Tumors ◽  
Infrared Spectroscopic Study ◽  
Human Breast ◽  
Breast Tumor Cell ◽  
Infrared Spectroscopic

Depletion of cartilage collagen fibrils in mice carrying a dominant negative Col2a1 transgene affects chondrocyte differentiation

2003 ◽  
Vol 285 (6) ◽  
pp. C1504-C1512 ◽  
Author(s):  
Ottavia Barbieri ◽  
Simonetta Astigiano ◽  
Monica Morini ◽  
Sara Tavella ◽  
Anna Schito ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Bone Growth ◽  
Collagen Type ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Collagen Fibrils ◽  
Dominant Negative ◽  
Differentiation Markers ◽  
Altered Expression ◽  
Dominant Negative Mutation

We have generated transgenic mice harboring the deletion of exon 48 in the mouse α1(II) procollagen gene ( Col2a1). This was the first dominant negative mutation identified in the human α1(II) procollagen gene ( COL2A1). Patients carrying a single allele with this mutation suffer from a severe skeletal disorder called spondyloepiphyseal dysplasia congenita (SED). Transgenic mice phenotype was neonatally lethal with severe respiratory failure, short bones, and cleft palate. Transgene mRNA was expressed at high levels. Growth plate cartilage of transgenic mice presented morphological abnormalities and reduced number of collagen type II fibrils. Chondrocytes carrying the mutation showed altered expression of several differentiation markers, like fibroblast growth factor receptor 3 (Fgfr3), Indian hedgehog (Ihh), runx2, cyclin-dependent kinase inhibitor P21CIP/WAF (Cdkn1a), and collagen type X (Col10a1), suggesting that a defective extracellular matrix (ECM) depleted of collagen fibrils affects chondrocytes differentiation and that this defect participates in the reduced endochondral bone growth observed in chondrodysplasias caused by mutations in COL2A1.

Altered expression and localization of PKC eta in human breast tumors

2001 ◽  
Vol 68 (3) ◽  
pp. 211-223 ◽  
Author(s):  
P.A. Masso-Welch ◽  
J.S. Winston ◽  
S. Edge ◽  
K.M. Darcy ◽  
H. Asch ◽  
...  
Keyword(s):  
Breast Tumors ◽  
Human Breast ◽  
Altered Expression

scholarly journals A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer

2022 ◽  
Author(s):  
Sandra Tietscher ◽  
Johanna Wagner ◽  
Tobias Anzeneder ◽  
Claus Langwieder ◽  
Martin Rees ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Breast Tumors ◽  
Cell Phenotype ◽  
T Cell Exhaustion ◽  
Human Breast ◽  
Cell Exhaustion

Abstract Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but the causes and implications of T cell exhaustion in breast tumors are not well understood. Here, we used single-cell transcriptomics combined with imaging mass cytometry to comprehensively study exhausted and non-exhausted immune environments in human breast tumors, with a focus on Luminal subtypes. We found that the presence of a PD-1high exhaustion-like T cell phenotype was indicative of an inflammatory immune environment with a characteristic cytotoxic profile and spatial features. Accumulation of natural killer T cells and increased myeloid cell activation in exhausted immune environments provide further support for tissue inflammation in these environments. Consistent with this, our comprehensive map of cellular interactions within the breast tumor microenvironment revealed elevated immunomodulatory, chemotactic, and cytokine signaling in exhausted environments. These data reveal fundamental differences between exhausted and non-exhausted immune environments within Luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I – but not PD-L1 – on tumor cells are strong distinguishing features between these environments; these factors are potential new biomarkers for patient stratification.

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