Modeling molecular development of breast cancer in canine mammary tumors

Abstract

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue, benign and malignant tumors from each patient. We demonstrated human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We demonstrated that multiple-histological-samples per patient is necessary to effectively capture these progressionrelated signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework. molecular progression signal (Crawford and Oleksiak 2007;Storey et al. 2007;Hughes et al. 2015). In vitro approaches using human cell lines have been used to control for this sample heterogeneity; however, they are not fully reflective of in vivo tumor progression, including the effects of the microenvironment and the immune system (Gillet et al. 2011;Stein et al. 2004).The (in vivo) murine model of breast cancer has proven incredibly useful in deciphering cancer mechanisms, however, it requires experimental modification of the host via genetic modification (transgenic mice) or the transplantation of foreign tissue (xenografts) (Rangarajan and Weinberg 2003; Boone et al. 2015), which alters the tumor dynamics (Ben-David et al. 2017).Canine mammary tumor (CMT) is a promising emerging model for studying naturally occurring breast tumors (Klopfleisch et al. 2011;Liu et al. 2014;Pinho et al. 2012). CMTs and human breast cancer (BRCA) have similar histopathological profiles, including incidence rates, relationship with age and body mass index, hormonal influence, and clinical presentation as demonstrated in many clinical and smaller scale studies (Cekanova and Rathore 2014;Paoloni and Khanna 2008;Rowell et al. 2011;Kol et al. 2015;Kristiansen et al. 2016). Canine simple carcinomas share especially strong similarities with human breast cancer in terms of both histological and genetic features (Liu et al. 2014). Additionally, BRCA and CMT share chromosomal abnormalities such as copy number variations in several key breast cancer marker genes like MYC and PTEN (Borge et al. 2015). A significant advantage of the canine model is the high incidence of multiple naturally occurring tumors in the same patient (Sorenmo et al. ...

Comparative analysis of the molecular subtype landscape in canine and human mammary gland tumors

“…S5a) and a majority of these showed a basallike gene expression profile in line with our main results. The second dataset (Graim et al) [9] consists of multiple tumors from each patient, including a substantial number of benign tumors, and none of those showed a distinct basal-like phenotype (Supplementary Fig. S5b), also in line with our findings in the main dataset.…”

“…There is, therefore, a need for animal models that mimic human breast cancer more precisely. The dog has emerged as a potential candidate and has been demonstrated to be an efficient model for human cancers [3][4][5][6], including breast cancer [7][8][9].…”

“…The PAM50 method, including the 50 genes and the associated centroids were identified from studies of human breast cancer, however, this method captures core biological characteristics of tumors that are relevant in both humans and dogs. There are few studies on the applicability and relevance of PAM50 subtyping in canine mammary gland tumors; however, in a study by Graim et al, PAM50 subtyping was performed on CMGTs from 16 canine patients [ 9 ]. They showed considerable resemblance between canine and human tumors of the same subtype at both the transcriptional and mutational levels.…”

Dynamic Enhanced Magnetic Resonance Imaging versus Ultrasonic Diffused Optical Tomography in Early Diagnosis of Breast Cancer

“…Tumor tissue has a good environment of blood flow supply to meet its efficient energy metabolism and supply and provide nutrition delivery, immune regulation inhibition, metabolite exclusion and cytokine secretion, and therefore, the state of angiogenesis often determines the malignant biological behaviors such as tumor growth, infiltration and metastasis [ 20 , 21 ]. Dynamic enhancement technology enables the analysis of functional information such as cellular composition, vascular permeability, interstitial pressure, blood flow supply, and extracellular space from a hemodynamic perspective through the dynamic distribution process of contrast agent inside the tumor [ 22 – 24 ].…”

Large Animal Models of Breast Cancer

“…Development of CMTs is hormone dependent and showed dysregulated expression of BRCA1, BRCA2 and TP53 (25)(26)(27), analogous to human BC. Transcriptional analysis of CMTs demonstrated pathways that are active in human cancer, including those involved with cell cycle regulation, apoptotic signaling, immune functions, endoplasmic reticulum stress, angiogenesis, and cell migration (38). Approximately 25% of the genetic alterations in metastatic CMTs were associated with human mammary cancer (39).…”