ANK2 Hypermethylation in Canine Mammary Tumors and Human Breast Cancer

Canine mammary tumors (CMT) constitute the most common tumor types found in female dogs. Understanding this cancer through extensive research is important not only for clinical veterinary applications, but also in the scope of comparative oncology. The use of DNA methylation as a biomarker has been noted for numerous cancers in the form of both tissue and liquid biopsies, yet the study of methylation in CMT has been limited. By analyzing our canine methyl-binding domain sequencing (MBD-seq) data, we identified intron regions of canine ANK2 and EPAS1 as differentially methylated regions (DMGs) in CMT. Subsequently, we established quantitative methylation specific PCR (qMSP) of ANK2 and EPAS1 to validate the target hypermethylation in CMT tissue, as well as cell free DNA (cfDNA) from CMT plasma. Both ANK2 and EPAS1 were hypermethylated in CMT and highlighted as potential tissue biomarkers in CMT. ANK2 additionally showed significant hypermethylation in the plasma cfDNA of CMT, indicating that it could be a potential liquid biopsy biomarker as well. A similar trend towards hypermethylation was indicated in HBC at a specific CpG of the ANK2 target on the orthologous human region, which validates the comparative approach using aberrant methylation in CMT.

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Naturally-Occurring Canine Mammary Tumors as a Translational Model for Human Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.00617 ◽

2020 ◽

Vol 10 ◽

Cited By ~ 8

Author(s):

Mark Gray ◽

James Meehan ◽

Carlos Martínez-Pérez ◽

Charlene Kay ◽

Arran K. Turnbull ◽

...

Keyword(s):

Breast Cancer ◽

Human Breast Cancer ◽

Mammary Tumors ◽

Human Breast ◽

Translational Model ◽

Naturally Occurring ◽

Canine Mammary Tumors

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Plasticity of Cloned Canine Mammary Spindle Cell Tumor, Osteosarcoma and Carcinoma Cells

Veterinary Pathology ◽

10.1354/vp.45-6-803 ◽

2008 ◽

Vol 45 (6) ◽

pp. 803-815 ◽

Cited By ~ 7

Author(s):

H. Wensman ◽

V. Flama ◽

G. Pejler ◽

E. Hellmén

Keyword(s):

Nude Mice ◽

Spindle Cell ◽

Expression Patterns ◽

Mammary Tumors ◽

Tumor Formation ◽

Cell Tumor ◽

Spindle Cell Tumor ◽

Keratin Expression ◽

Canine Mammary Tumors ◽

Tumor Types

Female dogs are frequently affected by mammary tumors, both carcinomas and sarcomas. The mechanisms behind mammary-tumor formation and the high degree of heterogeneity are not understood. To provide insight into this issue, it is important to determine the properties of the cells forming the different types of tumors. One question is if individual neoplastic cells can give rise to phenotypically distinct tumor types, i.e., show plasticity. We studied 3 different tumors (a spindle-cell tumor, an osteosarcoma, and a carcinoma) and followed the change of lineage marker expression between the primary canine mammary tumors, the clones derived from the corresponding tumors and in tumors generated after inoculation of tumor clones into nude mice ( n = 75). Inoculation of clones derived from the spindle-cell tumor gave rise to spindle-cell tumors in nude mice. Several of these contained bone tissue, a sign of plasticity. Clones derived from the osteosarcoma were negative for a panel of lineage markers but, when inoculated into nude mice, they were able to form bone, again a sign of plasticity. In contrast to the primary carcinoma, most of the clones derived thereof lacked keratin expression, but keratin expression was recovered in most of the tumors formed after inoculation of clones into nude mice. Moreover, tumors generated from the carcinoma clones, in contrast to the primary tumor, were positive for smooth-muscle-cell markers. Our results point to plasticity in canine mammary tumors, as shown both by morphologic criteria and by expression patterns for lineage specific markers.

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PKM2 in Canine Mammary Tumors: Parallels to Human Breast Cancer

Comparative Medicine ◽

10.30802/aalas-cm-20-000013 ◽

2020 ◽

Vol 70 (4) ◽

pp. 349-354

Author(s):

Hyo-Ju Lee ◽

Hyo-Jeong Han ◽

Ji-Young Lee ◽

Woo-Chan Son

Keyword(s):

Breast Cancer ◽

Human Breast Cancer ◽

Aerobic Glycolysis ◽

Prognostic Significance ◽

Tumor Grade ◽

Mammary Tumors ◽

Neoplastic Disease ◽

Human Breast ◽

Rate Limiting Step ◽

Canine Mammary Tumors

PKM2 is a pyruvate kinase isoform that is the final and rate-limiting step in aerobic glycolysis in tumor cells. Increased expression of PKM2 has been detected in human cancers. The present study examined the expression of PKM2 in canine mammary tumors and assessed its prognostic significance. Paraffin sections of 5 adenomas, 67 carcinomas, and 5 samples of nonneoplastic hyperplasia from 77 dogs, aged 8 to 18 y, were evaluated. Significantly higher levels of PKM2 were detected among the carcinomas compared with all other tissues examined. The level of PKM2 expression in carcinoma tissue correlated positively with the tumor grade. These findings suggest that PKM2 may have a similar role in canine mammary tumors to its role in human breast cancer. As such, canine mammary tumors may be useful models for studies focused on the progression of human neoplastic disease.

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A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors

BioMed Research International ◽

10.1155/2014/130894 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 33

Author(s):

Maria Isabel Carvalho ◽

Isabel Pires ◽

Justina Prada ◽

Felisbina L. Queiroga

Keyword(s):

Breast Cancer ◽

T Lymphocytes ◽

Human Breast Cancer ◽

Survival Rates ◽

Mammary Tumors ◽

Treg Cells ◽

Th2 Cells ◽

Human Breast ◽

Canine Mammary Tumors ◽

As Relationship

Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.

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Immunohistochemical Analysis of Na+/K+-ATPase and Bone Morphogenetic Protein-2 Expressions in Both Parenchymal and Stromal Cells from Benign and Malignant Canine Mammary Tumors

10.21203/rs.3.rs-431238/v1 ◽

2021 ◽

Author(s):

ozlem ozmen

Keyword(s):

Stromal Cells ◽

Malignant Tumors ◽

Breast Tumors ◽

Mammary Tumors ◽

Bone Morphogenetic Protein 2 ◽

Mammary Tissue ◽

Benign Tumors ◽

Ion Pump ◽

Human Breast ◽

Canine Mammary Tumors

Abstract Canine mammary tumors are the most common type of dog tumor, and they are similar to human breast tumors. Na+/K+-ATPase is a common plasma membrane ion pump with important physiological and pathophysiological functions. In mammary tumors, the tumor microenvironment was composed of a heterogeneous population of tumor cells and nearby endogenous stromal cells. Bone morphogenetic proteins (BMPs) regulate fetal development, tissue homeostasis and differentiation, and a variety of cellular functions. The purpose of this study is to examine the immunohistochemical expression of Na+/K+-ATPase and BMP-2 in tumoral and stromal cells from benign and malignant canine mammary tumors. In this study, ten benign and ten malignant mammary tumors from the archives of the Department of Pathology were used, with five normal breast tissues serving as controls. The results of the revealed that tumors had higher levels of Na+/K+-ATPase and BMP-2 expressions than normal mammary tissue. While both markers were expressed negatively or mildly in benign tumors, they increased significantly in malignant tumors. Both Na+/K+-ATPase and BMP-2 are expressed by tumoral and stromal cells in canine mammary tumors. When compared to compared to BMP-2, Na+/K+-ATPase expression was found to be more severe. This study found that Na+/K+-ATPase and BMP-2 can be used as markers of malignancy in canine mammary tumors and that stromal cells also play an important role in tumor progression. These findings also indicated that Na+/K+-ATPase and BMP-2 may be used for early diagnosis or as a potential target for treatment of canine and human breast tumors in the future.

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Changes in Serum and Salivary Proteins in Canine Mammary Tumors

Animals ◽

10.3390/ani10040741 ◽

2020 ◽

Vol 10 (4) ◽

pp. 741

Author(s):

Lorena Franco-Martínez ◽

Andrea Gelemanović ◽

Anita Horvatić ◽

María Dolores Contreras-Aguilar ◽

Roman Dąbrowski ◽

...

Keyword(s):

Proteomic Analysis ◽

Mammary Tumors ◽

Human Breast ◽

Heavy Chains ◽

Proteomic Data ◽

Canine Mammary Tumors ◽

Paired Serum ◽

Immunoglobulin Gamma ◽

First Time ◽

Sample Set

The aim of this study was to evaluate changes in serum and saliva proteomes in canine mammary tumors (CMT) using a high-throughput quantitative proteomic analysis in order to potentially discover possible biomarkers of this disease. Proteomes of paired serum and saliva samples from healthy controls (HC group, n = 5) and bitches with CMT (CMT group, n = 5) were analysed using a Tandem Mass Tags-based approach. Twenty-five dogs were used to validate serum albumin as a candidate biomarker in an independent sample set. The proteomic analysis quantified 379 and 730 proteins in serum and saliva, respectively. Of those, 35 proteins in serum and 49 in saliva were differentially represented. The verification of albumin in serum was in concordance with the proteomic data, showing lower levels in CMT when compared to the HC group. Some of the modulated proteins found in the present study such as haptoglobin or S100A4 have been related to CMT or human breast cancer previously, while others such as kallikrein-1 and immunoglobulin gamma-heavy chains A and D are described here for the first time. Our results indicate that saliva and serum proteomes can reflect physiopathological changes that occur in CMT in dogs and can be a potential source of biomarkers of the disease.

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Intraoperative near-infrared imaging can identify canine mammary tumors, a spontaneously occurring, large animal model of human breast cancer

PLoS ONE ◽

10.1371/journal.pone.0234791 ◽

2020 ◽

Vol 15 (6) ◽

pp. e0234791

Author(s):

Andrew Newton ◽

Jarrod Predina ◽

Michael Mison ◽

Jeffrey Runge ◽

Charles Bradley ◽

...

Keyword(s):

Breast Cancer ◽

Animal Model ◽

Human Breast Cancer ◽

Near Infrared ◽

Infrared Imaging ◽

Mammary Tumors ◽

Large Animal Model ◽

Large Animal ◽

Human Breast ◽

Canine Mammary Tumors

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Faculty Opinions recommendation of A Comparison of Fresh Frozen vs. Formalin-Fixed, Paraffin-Embedded Specimens of Canine Mammary Tumors via Branched-DNA Assay.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726361618.793528010 ◽

2017 ◽

Author(s):

Alexandre Alanio

Keyword(s):

Mammary Tumors ◽

Dna Assay ◽

Branched Dna ◽

Canine Mammary Tumors ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Fresh Frozen ◽

Formalin Fixed

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Overexpression of Mucin 1 Suppresses the Therapeutical Efficacy of Disulfiram against Canine Mammary Tumor

Animals ◽

10.3390/ani11010037 ◽

2020 ◽

Vol 11 (1) ◽

pp. 37

Author(s):

Ying Zhao ◽

Zixiang Lin ◽

Zhaoyan Lin ◽

Chaoyu Zhou ◽

Gang Liu ◽

...

Keyword(s):

Mammary Tumor ◽

Mammary Tumors ◽

Expression Level ◽

Canine Mammary Tumor ◽

Wild Type ◽

Mucin 1 ◽

Mammary Tumor Cell ◽

Mammary Tumor Cell Line ◽

Canine Mammary Tumors ◽

Wild Type Control

Mucin 1 (MUC1), a transmembrane protein, is closely associated with the malignancy and metastasis of canine mammary tumors; however, the role of overexpressed MUC1 in the development of cancer cells and response to drug treatment remains unclear. To address this question, we developed a new canine mammary tumor cell line, CIPp-MUC1, with an elevated expression level of MUC1. In vitro studies showed that CIPp-MUC1 cells are superior in proliferation and migration than wild-type control, which was associated with the upregulation of PI3K, p-Akt, mTOR, Bcl-2. In addition, overexpression of MUC1 in CIPp-MUC1 cells inhibited the suppressing activity of disulfiram on the growth and metastasis of tumor cells, as well as inhibiting the pro-apoptotic effect of disulfiram. In vivo studies, on the other side, showed more rapid tumor growth and stronger resistance to disulfiram treatment in CIPp-MUC1 xenograft mice than in wild-type control. In conclusion, our study demonstrated the importance of MUC1 in affecting the therapeutical efficiency of disulfiram against canine mammary tumors, indicating that the expression level of MUC1 should be considered for clinical use of disulfiram or other drugs targeting PI3K/Akt pathway.

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