Transcriptome Signatures of Canine Mammary Gland Tumors and Its Comparison to Human Breast Cancers

Abstract

Breast cancer (BC)/mammary gland carcinoma (MGC) is the most frequently diagnosed and leading cause of cancer-related mortality in both women and canines. To better understand both canine MGC and human BC-specific genes, we sequenced RNAs obtained from eight pairs of carcinomas and adjacent normal tissues in dogs. By comprehensive transcriptome analysis, 351 differentially expressed genes (DEGs) were identified in overall canine MGCs. Based on the DEGs, comparative analysis revealed correlation existing among the three histological subtypes of canine MGC (ductal, simple, and complex) and four molecular subtypes of human BC (HER2+, ER+, ER&HER2+, and TNBC). Eight DEGs shared by all three subtypes of canine MGCs had been previously reported as cancer-associated genes in human studies. Gene ontology and pathway analyses using the identified DEGs revealed that the biological processes of cell proliferation, adhesion, and inflammatory responses are enriched in up-regulated MGC DEGs. In contrast, fatty acid homeostasis and transcription regulation involved in cell fate commitment were down-regulated in MGC DEGs. Moreover, correlations are demonstrated between upstream promoter transcripts and DEGs. Canine MGC- and subtype-enriched gene expression allows us to better understand both human BC and canine MGC, yielding new insight into the development of biomarkers and targets for both diseases.

Molecular Parallelisms and Divergences Between Human and Canine Cancers Would a dog be an appropriate experimental model for human cancers?

“…However, some new Ensembl genes were identified in canine mammary cancer and some of known cancer as a down-regulated in the dog but are known to be up-regulated in human breast cancer. These results are not consistent with previous studies, because we studied all subtypes of canine mammary cancer 17 . These results might represent similarities and discrepancies that exist between human breast cancer and canine mammary cancer.…”

“…Since, many studies have been performed in comparison to human breast cancers and canine mammary at the transcriptome level. Thus, our results reveal the similarities and discrepancies between human breast cancer and canine mammary cancer 17 .…”

Alternative methylation of intron motifs is associated with cancer-related gene expression in both canine mammary tumor and human breast cancer

“…All of these target genes, hyper-and hypomethylated in CMT, were reversely correlated to gene expression. RNA expression levels of the candidate genes were obtained from our previous transcriptome data [23] and an anti-correlation was shown by (Fig. 5g, h).…”

“…The study of CMT has gained increasing importance not only for animal welfare but also for better understanding of HBC. Over the past decade, comparative studies of CMT and HBC have been conducted at the genome and transcriptome levels using high-throughput sequencing data and have presented similarities and discrepancies existing between CMT and HBC [23,25]. However, a comprehensive analysis of the genome-wide methylome in CMT and its comparison with the HBC methylome had not been studied yet.…”

“…Furthermore, CMT's molecular characteristics, including several subtype molecular markers such as steroid receptor, epidermal growth factor (EGF), and proliferation markers, are also similar to HBC [22]. Recently, we reported a transcriptome signature in CMT [23] and other high-throughput sequencing studies on the aspects of CMT have been reported [24,25]. However, no comprehensive genome-wide methylome profiles that are comparable to studies in HBC have been uncovered yet.…”