Abstract
There are many factors which make canine cancer like cancer in humans. The occurrence of spontaneous mammary tumors in pet dogs, tumor genetics, molecular targets and exposure to the same environmental risk factors are among these factors. Therefore, the study of canine cancer can provide useful information to the oncology field. This study aimed to establish and characterize a panel of primary mixed cell cultures obtained from spontaneous canine mammary tumors. Eight established cell cultures obtained from one normal mammary gland, one complex adenoma, one mixed adenoma, two complex carcinomas and two mixed carcinomas were analyzed. The gene expression levels of classic molecular cancer players such as fibroblast growth factor receptor (FGFR) 2, breast cancer (BRCA) 1, BRCA2 and estrogen receptor (ESR) 1 were evaluated. For the first time, three orphan nuclear receptors, estrogen-related receptors (ERRs) α, β and γ were studied in canine mammary cancer. The highest expression level of ERRα was observed in complex carcinoma-derived cell culture, while the highest levels of ERRβ and γ were observed in cells derived from a mixed carcinoma. Meanwhile, complex carcinomas presented the highest levels of expression of ESR1, BRCA1 and FGFR2 among all samples. BRCA2 was found exclusively in complex adenoma. The transcription factor GATA3 had its highest levels in mixed carcinoma samples and its lowest levels in complex adenoma. Proliferation assays were also performed to evaluate the mixed cell cultures response to ER ligands, genistein and DES, both in normoxia and hypoxic conditions. Our results demonstrate that morphological and functional studies of primary mixed cell cultures derived from spontaneous canine mammary tumors are possible and provide valuable tool for the study of various stages of mammary cancer development.
Highlights
The availability of pre-clinical animal models for human breast cancer represents a relevant challenge in the research of this type of neoplasm
The evaluation of the cell cycle has revealed very similar proliferation profiles for the mixed carcinomas with approximately 80% of cells in G1 phase and 10% of the cells in sub G1 phase; for the complex carcinomas with nearly 80% of cells in G1 and 10% of cells in S phase
Analysis of the ratio between epithelial and myoepithelial markers in all samples indicated an inverse correlation between epithelial and myoepithelial markers in normal mammary epithelium: higher expression of myosin heavy chain 11 (MYH11) transcripts in MAd; higher expression of MUC1 transcripts in Simple Carcinoma (SCa); higher expression of MUC1 transcripts in carcinoma 1 (CCa1); balanced amount of epithelial and myoepithelial markers in carcinoma 2 (CCa2) and MCa1, and higher expression of MUC1 transcripts in MCa2. These results show that complex and mixed carcinomas have different ratios within the same tumor subtype, raising the possibility that the prevalence of one cell type on the other could interfere in the behavior of those primary mixed cell cultures
Summary
The availability of pre-clinical animal models for human breast cancer represents a relevant challenge in the research of this type of neoplasm. Beyond the evolutionary distance between humans and mice, additional differences can be originated from induced genetic modifications, as in transgenic mice, or from the modified presence of components of normal adjacent tissue, as in the case of tumor transplants in mice [3, 4, 5, 6]. The limitation of mice models for the oncology field is an obstacle to overcome. One alternative for this issue relies on the fact that naturally occurring cancers in pet dogs and humans share many features, including histological appearance, tumor genetics, molecular targets, biological behavior and response to conventional therapies [7, 8, 9, 10, 11]. Comparative histologic analyses indicate that the observed intra-tumor heterogeneity in human mammary tumors occurs in canine tumors [16]
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