Reduction of phosphorylated signal transducer and activator of transcription-5 expression in feline mammary carcinoma

Abstract

Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in various normal physiological cellular processes. Moreover, STATs have been recently identified as novel therapeutic targets for various human tumors. STAT3, STAT5a, and STAT6 have been suggested to be involved in tumorigenesis in human breast cancer. Owing to the similarity between feline mammary carcinomas (FMCs) and human breast cancers, these factors may play an important role in FMCs. However, studies on the expression of STATs in animal tumors are limited. Therefore, in this study, we aimed to characterize the expression of total STAT5 (tSTAT5) and phosphorylated STAT5 (pSTAT5) in FMCs, feline mammary adenomas, non-neoplastic proliferative mammary gland lesions, and normal feline mammary glands using immunohistochemistry. High expression of tSTAT5 was observed in the cytoplasm of all the samples assessed in this study. Moreover, high expression of tSTAT5 was observed in the nucleus; however, its levels varied depending on the lesion. The percentage of pSTAT5-nuclear positive cells varied among normal feline mammary glands (40.1 ± 25.1%), and non-neoplastic lesions, including mammary hyperplasia (43.2 ± 28.6%) and fibroadenomatous changes (18.0 ± 13.6%). Moreover, the percentage of pSTAT5-nuclear-positive cells in feline mammary adenomas was 24.5 ± 19.2%, which was significantly reduced in feline mammary carcinomas (2.4 ± 5.6%), regardless of histopathological subtype. This study suggests that decreased STAT5 activity may be involved in the development and malignant progression of feline mammary carcinomas.

Keywords: feline mammary carcinoma; immunohistochemistry; signal transducers and activator of transcription-5.

Fig. 1.

Immunohistochemical features of the total-signal transducer and activator of transcription 5a (tSTAT5) in the non-neoplastic and neoplastic mammary glands. The tSTAT5 is strongly positive in the cytoplasm and nucleus of the secretory epithelial cells and ductal cells of the mammary ducts in normal (A), hyperplastic mammary gland (B), and lesion with fibroadenomatous changes (C). Moderate tSTAT5 expression is observed in the cytoplasm and strong tSTAT5 expression is observed in the nucleus in feline mammary adenoma samples (D). The expression of tSTAT5 is weak to moderate in the cytoplasm and moderate in the nucleus in feline mammary carcinomas (E and F). A myoepithelial cell with tSTAT5 expression is shown in the inset of (C) (arrowhead). The inset in each figure is the enlarged region of the non-neoplastic and neoplastic mammary lesions. (D) Simple adenoma. (E) Tubular carcinoma. (F) Comedocarcinoma. Scale=50 μm (A, C, and D). Scale=200 μm (B, E, and F).

Fig. 2.

Immunohistochemical features of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) in the non-neoplastic and neoplastic mammary glands. Weak to strong pSTAT5 expression is detected in the nuclei of secretory epithelial cells and ductal cells of normal (A), hyperplastic mammary gland (B), fibroadenomatous changes (C), and feline mammary adenoma (D). In contrast, very few tumor cells express pSTAT5 in feline mammary gland carcinoma (E and F). A myoepithelial cell with pSTAT5 expression is shown in the inset of (C) (arrowhead). The inset in each figure corresponds to the enlarged region of the non-neoplastic and neoplastic mammary lesions. (D) Simple adenoma. (E) Tubular carcinoma. (F) Comedocarcinoma. Scale=50 μm (A, C, and D). Scale=200 μm (B, E, and F).

Fig. 3.

The box-and-whisker plot of the percentage of positive cells for phosphorylated signal transducer and activator of transcription 5 (pSTAT5) in the non-neoplastic and neoplastic mammary glands. The comparison of the percent of the pSTAT5 nuclear positivity was statistically analyzed using the Steel–Dwass test, which revealed that the nuclear positivity rate of pSTAT5 was significantly lower in feline mammary carcinomas than in each group including normal mammary tissue, hyperplasia, fibroadenomatous change, and feline mammary adenomas. The bar crossing the box-and-whisker plot signifies the sample median, while the cross mark indicates the average (*P<0.05, P-values are indicated).