Immunohistochemical Detection of Mdm2 and p53 in Feline Mammary Gland Tumors

Abstract

ABSTRACT. The objective of this study was to evaluate nuclear reactivity of Mdm2 and p53 proteins by immunohistochemical means in feline mammary gland tumors; 12 adenomas which included 6 adenomatous lesions obtained from the tissue adjacent to adenocarcinomas, and 22 adenocarcinomas. Seven adenomas and 18 adenocarcinomas showed moderate or marked Mdm2 reactivity. Sixteen adenocarcinomas showed moderate to marked p53 reactivity, but 9 adenomas showed none. Discordant Mdm2 overexpression was found in 5 adenomas and 3 adenocarcinomas, although co-overexpression of Mdm2 and p53 was found in 15 adenocarcinomas. These results suggest that nuclear overexpression of Mdm2 is present in the tumors of early stage without p53 overexpression and related to feline mammary gland tumorigenesis. Nuclear overexpression of p53 is more frequent in adenocarcinomas, but not in adenomas. KEY WORDS: feline mammary tumor, Mdm2, p53.J. Vet. Med. Sci. 68(5): 421-425, 2006 Mammary neoplasm is the third most common tumor, following lymphoid and cutaneous neoplasms in cats and simple type adenocarcinoma, and complex type tumor and myoepithelioma are found rarely [12]. The molecular and genetic events contributing to feline mammary gland tumorigenesis are largely unknown.Mdm2 (murine double minute-2) gene was first cloned as an amplified gene in a spontaneously transformed mouse 3T3 DM cell line [9]. Mdm2 has been shown to interact with a group of cell cycle-related proteins, including the retinoblastoma protein [19], the transcription factor E2F1 [32], and transforming growth factor-beta [28]. Mdm2 is frequently overexpressed in soft tissue sarcomas in human beings [6] and dogs [25,27], and also in some human epithelial neoplasms, such as those of the breast [10,18] The function of p53 tumor suppressor is a principal mediator of growth arrest, senescence, and apoptosis in response to a broad array of cellular damage [17,31]. Mdm2 protein binds to p53 protein, and both proteins regulate each other; one effect is to inhibit the transcriptional transactivation activity of p53, resulting in negative regulation of the tumor suppression function of p53 [21,30]. p53 protein regulates Mdm2 gene at the level of transcription by an intronic promotor. This creates a feedback loop that regulates both the activity of p53 protein and the expression of Mdm2 gene [21,30]. Overexpression of p53 protein has been reported in feline mammary gland tumors and squamous cell carcinomas [22], and in human malignant epithelial tumors of the breast [3], stomach [13], kidney [11], and liver [7].The expression of Mdm2 in feline mammary gland tumors has not been studied. The purpose of this study was to better understand the mechanisms of feline mammary gland tumorigenesis by immunohistochemical means for the nuclear reactivity of Mdm2 and p53 proteins and the relationship between expression of these molecules. MATERIALS AND METHODS Tumors:The samples were collected from feline mammary tumors removed surgically during a 5-year period at Yamaguchi University. The samp...

Felis catus papillomavirus type-2 E6 binds to E6AP, promotes E6AP/p53 binding and enhances p53 proteasomal degradation

“…The same reaction was run on slides with primary antibodies omitted as negative control, feline mammary adenocarcinoma was used as positive control for p53 antibody 21 .…”

Prognostic Evaluation of Feline Mammary Carcinomas

“…[47][48][49] Different immunohistochemical protocols, scoring systems, and the absence of a standardized cutoff value for p53 positivity may be responsible for this variability. 62,64,66,67,80 In one study with follow-on data, there was no association between p53 mutations and 1-year postsurgical survival. 80 Furthermore, no significant correlation has been found between p53 expression and histologic grade, ER status, Mdm2, cyclin A, cyclin D, TopBP1 (topoisomerase IIb binding protein 1), and HER-2 expression (Table 1).…”

“…80 Furthermore, no significant correlation has been found between p53 expression and histologic grade, ER status, Mdm2, cyclin A, cyclin D, TopBP1 (topoisomerase IIb binding protein 1), and HER-2 expression (Table 1). 62,66,80 Standardization of the IHC protocol and scoring system and more extensive follow-up studies are required to evaluate the role of p53 in FMCs.…”

Early Detection, Aggressive Therapy

“…64 Protein p53 mutation and nuclear accumulation has been detected immunohistochemically in 18.9% of feline mammary carcinomas, and it was shown that p53 immunohistochemical reactivity was significantly lower in adenomas compared with adenocarcinomas. 63,65 Other studies demonstrated overexpression of p53 in 32.5-33% of carcinomas. 66,67 RON Macrophage-stimulating protein receptor (RON) is a member of the family of receptor tyrosine kinases that stimulate invasive properties of carcinoma cells.…”