Abstract
Obesity is an established risk factor for breast cancer in post-menopausal women, being associated with elevated serum levels of leptin. Although overweight is a common condition in cat, the role of leptin and its receptor in feline mammary carcinoma remains unsettled. In this study, serum leptin and leptin receptor (ObR) levels were investigated in 58 cats with mammary carcinoma and compared with those of healthy animals, as were the expression levels of leptin and ObR in tumor tissues. The results showed that the Free Leptin Index is significantly decreased in cats with mammary carcinoma (p = 0.0006), particularly in those with luminal B and HER2-positive tumors, and that these animals also present significantly lower serum leptin levels (p < 0.0001 and p < 0.005, respectively). Interestingly, ulcerating tumors (p = 0.0005) and shorter disease-free survival (p = 0.0217) were associated to serum leptin levels above 4.17 pg/mL. In contrast, elevated serum ObR levels were found in all cats with mammary carcinoma (p < 0.0001), with levels above 16.89 ng/mL being associated with smaller tumors (p = 0.0118), estrogen receptor negative status (p = 0.0291) and increased serum levels of CTLA-4 (p = 0.0056), TNF-α (p = 0.0025), PD-1 (p = 0.0023), and PD-L1 (p = 0.0002). In tumor samples, leptin is overexpressed in luminal B and triple-negative carcinomas (p = 0.0046), whereas ObR is found to be overexpressed in luminal B tumors (p = 0.0425). Altogether, our results support the hypothesis that serum levels of leptin and ObR can be used as biomarkers of specific feline mammary carcinoma subtypes, and suggests the use of leptin antagonists as a therapeutic tool, reinforcing the utility of the cat as a cancer model.
Highlights
Feline mammary carcinoma (FMC) is a high prevalence disease (12–40% of all tumors in cat) that shows similar clinicopathological and genetic features [1], comparing to human breast cancer [2], supporting its use in comparative oncology studies [3, 4], and allowing to improve therapeutic protocols for women and cats [5]
Spontaneous FMC has been proposed as a suitable model for human breast cancer studies, the role of the leptin/ObR
The healthy group presented a mean age lower than the tumor group, and despite what is reported in human and rats [58, 59], the results obtained demonstrated that cats with mammary carcinoma have a reduced Free Leptin Index (FLI) in comparison to the healthy group (p = 0.0006), due to the increase in serum ObR levels [60], and suggesting that diseased animals may have decreased soluble leptin levels, as reported in pre-menopausal women with breast cancer [61] and colon cancer patients [62]
Summary
Feline mammary carcinoma (FMC) is a high prevalence disease (12–40% of all tumors in cat) that shows similar clinicopathological and genetic features [1], comparing to human breast cancer [2], supporting its use in comparative oncology studies [3, 4], and allowing to improve therapeutic protocols for women and cats [5]. Leptin expression is modulated by fat mass, with healthy cats showing lower serum leptin levels than obese animals [12], as reported in humans [13, 14]. This protein is mainly secreted by adipocytes, it can be expressed by pathologically altered cells, such as cancer cells [19, 20]. Leptin overexpression is detected in breast cancer cells and neighboring adipocytes, contrasting with normal breast glandular epithelial cells [15, 25], promoting the expression of several tissue factors [26], which suggest an oncogenic role for this adipocytokine [14]. In overweight human patients a positive correlation was found between leptin overexpression in the tumor microenvironment and estrogen receptor (ER) positive breast cancer, and with a human epidermal growth factor receptor 2 (HER 2)-positive status frequently related to a more invasive tumor phenotype [27]
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