Serum and Tissue Expression Levels of Leptin and Leptin Receptor Are Putative Markers of Specific Feline Mammary Carcinoma Subtypes

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.

Adipocyte-Derived Adipokines and Other Obesity-Associated Molecules in Feline Mammary Cancer

“…Since the human breast is primarily composed of adipose tissue and breast cancer cells come into direct contact with these cells, obesity has been explored as a modulator of breast cancer [ 4 ]. Research has determined that obesity is a risk factor for breast cancer in post-menopausal women [ 4 , 5 ]. Obese women are at higher risk for larger breast cancer tumors, lymph node metastasis, and death compared with women who are non-obese [ 4 ].…”

“…In domestic cats of Western countries, obesity has been identified as the most common health disorder [ 6 ]. It is estimated that 30–40% of domestic cats are obese, with indoor, neutered cats above the age of 3 being at greatest risk of developing obesity [ 1 , 5 ]. Similarly to humans, obese cats are also at an increased risk of developing health disorders, such as endocrine and lipid metabolism disorders, lower urinary tract disease, gastrointestinal disease, dermatoses, and cancer [ 7 ].…”

“…A cancer of particular interest in cats is feline mammary cancer (FMC). FMC is the third most common neoplasia in cats, making up 12–40% of all tumors identified in cats [ 5 , 8 ]. This type of cancer shares many commonalities with human breast cancer; both diseases show similar molecular classification, epidemiology, and clinicopathological features [ 3 , 5 , 9 ].…”

“…FMC is the third most common neoplasia in cats, making up 12–40% of all tumors identified in cats [ 5 , 8 ]. This type of cancer shares many commonalities with human breast cancer; both diseases show similar molecular classification, epidemiology, and clinicopathological features [ 3 , 5 , 9 ]. As there is a high degree of similarity between FMC and breast cancer, and since breast cancer is well known to be influenced by obesity, it is important to determine whether obesity also influences the development of FMC [ 3 , 4 , 5 , 9 ].…”

“…This type of cancer shares many commonalities with human breast cancer; both diseases show similar molecular classification, epidemiology, and clinicopathological features [ 3 , 5 , 9 ]. As there is a high degree of similarity between FMC and breast cancer, and since breast cancer is well known to be influenced by obesity, it is important to determine whether obesity also influences the development of FMC [ 3 , 4 , 5 , 9 ]. This will aid in improving research design and allow for progress toward common goals that will benefit both species.…”