Abstract
The feline mammary carcinoma (FMC) is the third most common tumor in cat, sharing many clinicopathological features with human breast cancer and thus, considered a suitable model for comparative oncology. Due to its poor prognosis, further studies are required to improve the diagnostic accuracy and treatment of cats with spontaneous mammary carcinoma. Recently, it was reported that the overexpression of stromal cell-derived factor-1 (SDF-1) has great value in human breast cancer diagnosis, suggesting that diagnostic tools and therapies targeting the SDF-1 ligand can improve the clinical outcome. In this study, we aimed to evaluate if serum SDF-1 levels can also be used as a biomarker of mammary carcinoma in cats and to analyze if serum SDF-1 levels are associated with clinicopathological features, linked to a specific FMC subtype or correlated with the tumor expression of SDF-1 receptor, the chemokine C-X-C motif receptor 4 (CXCR4). Results showed that cats with mammary carcinoma had significantly higher serum SDF-1 levels than healthy controls (p=0.035) and ROC analysis revealed that the best cut-off value to differentiate sick from healthy animals was 2 ng/ml (specificity: 80%; sensitivity: 57%; AUC=0.715). Significant associations were also found between cats with elevated serum SDF-1 concentrations (≥ 2 ng/ml) and HER2-overexpressing mammary carcinomas (Luminal B-like and HER2-positive subtypes, p<0.0001), CXCR4-negative mammary carcinomas (p=0.027), mammary carcinomas with small size (<3 cm, p=0.027) and tumors with low Ki-67 expression (p=0.012). No statistical associations were found between serum SDF-1 levels and overall or disease-free survival. In summary, our results show that serum SDF-1 levels can be used as a biomarker of feline mammary carcinoma, especially in cats with HER2-overexpressing mammary tumors. Data suggest that targeted therapies against the SDF-1 ligand and/or its CXC4 receptor may be effective for the treatment of FMC, as described for human breast cancer, strengthening the concept that spontaneous feline mammary carcinoma is a suitable model for comparative oncology.
Highlights
The feline mammary carcinoma (FMC) is very common in cat (12-40% of all neoplasms), showing overexpression of the human epidermal growth factor receptor type II (HER2) protooncogene in 33%-60% of the cases [1,2,3,4,5]
We aimed to evaluate if serum stromal cell-derived factor-1 (SDF-1) levels can be used as a biomarker of mammary carcinoma in cats and to analyze if serum SDF-1 levels are associated with clinicopathological features, linked to a specific FMC subtype or correlated with the tumor expression of SDF-1 receptor, the chemokine C-X-C motif receptor 4 (CXCR4)
Data suggest that targeted therapies against the SDF-1 ligand and/or its CXC4 receptor may be effective for the treatment of FMC, as described for human breast cancer, strengthening the concept that spontaneous feline mammary carcinoma is a suitable model for comparative oncology
Summary
The feline mammary carcinoma (FMC) is very common in cat (12-40% of all neoplasms), showing overexpression of the HER2 protooncogene in 33%-60% of the cases [1,2,3,4,5]. Despite the efforts to understand the oncogenic mechanisms of breast cancer, the discovery of more accurate biomarkers and therapeutic targets are listed as research priorities [12] Considering this scenario, an increasing attention is given to a family of chemotactic molecules known as chemokines, which are secreted by a variety of stromal and epithelial cells, exerting its biological effects by interacting with G protein-coupled receptors (GPCR). Their binding to these receptors mediates leukocyte migration and adhesion to the tumor endothelial cells, regulating the tumor growth, angiogenesis and apoptosis [13, 14]. Some studies reported that breast cancer patients display increased serum SDF-1 levels, in particular patients with HER2-overexpressing breast tumors [40] and that serum SDF-1 concentration has prognostic value [19, 40,41,42,43,44]
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