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Immunohistochemical Analysis of Cyclin A, Cyclin D1 and P53 in Mammary Tumors, Squamous Cell Carcinomas and Basal Cell Tumors of Dogs and Cats

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Immunohistochemical Analysis of Cyclin A, Cyclin D1 and P53 in Mammary Tumors, Squamous Cell Carcinomas and Basal Cell Tumors of Dogs and Cats FULL PAPER Pathology Immunohistochemical Analysis of Cyclin A, Cyclin D1 and P53 in Mammary Tumors, Squamous Cell Carcinomas and Basal Cell Tumors of Dogs and Cats Yuichi MURAKAMI, Susumu TATEYAMA*, Anudep RUNGSIPIPAT, Kazuyuki UCHIDA and Ryoji YAMAGUCHI Department of Veterinary Pathology, Faculty of Agriculture, Miyazaki University, Nishi 1–1 Gakuen Kibana Dai, Miyazaki 889–2192, Japan (Received 18 October 1999/Accepted 25 March 2000) ABSTRACT. The involvement of cyclin A, cyclin D1 and p53 proteins in canine and feline tumorigenesis was analyzed immunohistochemically. In the present study, a total of 176 cases were examined, among which there were 108 canine cases (75 mammary lesions, 16 squamous cell carcinomas and 17 basal cell tumors) and 68 feline cases (43 mammary lesions, 20 squamous cell carcinomas and 5 basal cell tumors). Speckled nuclear staining for cyclin A was observed in 19/38 (50%) canine malignant mammary tumors and 18/37 (48.6%) feline mammary carcinomas, while this was not seen in benign mammary tumors of either dogs or cats. Marked intense nuclear cyclin A staining was seen in 7/16 (43.8%) canine squamous cell carcinomas and 18/20 (90.0%) feline squamous cell carcinomas. Only 3/17 (17.6%) canine basal cell tumors showed slight and scattered staining for cyclin A. Expression of cyclin D1 was very rare in both canine and feline tumors. Nuclear staining of p53 was found in 7/37 (18.9%) feline mammary carcinomas. Intense immunoreactivity for p53 was found in 6/16 (37.5%) canine squamous cell carcinomas and 8/20 (40%) feline squamous cell carcinomas. These results suggest that cyclin A may have a role in the proliferation of canine malignant mammary tumors, feline mammary carcinomas and squamous cell carcinomas of dogs and cats, and p53 may associate with the tumorigenesis of feline mammary carcinomas and squamous cell carcinomas of dogs and cats. KEY WORDS: canine, cyclin A, cyclin D1, feline, p53. J. Vet. Med. Sci. 62(7): 743–750, 2000 The critical role that the family of regulatory proteins G1 phase. Overexpression of cyclin D1 has been found in a known as cyclins play in eukaryotic cell cycle regulation is wide variety of human tumors, such as breast cancers [1, 3, 8, well established. Cyclins are categorized into three types; A- 13, 21, 24, 30, 39, 48], head and neck cancers [4, 26] and type, B-type, G1 cyclins (C-, D-, and E-types), that act by esophageal cancers [18,19, 32], sometimes due to gene ampli- forming a complex with cyclin dependent kinases (cdk) at var- fication. ious stages of the cell cycle. Phosphorylation of the retino- In human, the p53 tumor suppressor gene is located on the blastoma protein by these complexes leads to the release of a short arm of chromosome 17 and its protein product is a nega- variety of transcription factors, usually represented by E2F tive regulator of the cell cycle in the G1 phase. Mutations in family members, and is considered to be the major driving the p53 gene are the most frequent alteration in many types of event in the transition from G1 to S phase of the cell cycle. human malignancy, including lung, colon and breast cancers. Altered expression of several cyclins in human cancer has Recently, cDNAs for canine and feline p53 have been molec- been recognized in the past few years. ularly cloned [29, 43]. P53 mutation has been reported in Cyclin A, a protein of 60 kDa, binds independently to cdk2 canine mammary tumors [23], canine osteosarcomas [25, 42] in S to G2 phase, and cdk2/cdc2 in G2 to M phase, leading to and feline hematopoietic tumors [29], and besides the protein enzyme activation. Cyclin A is detectable in S phase, and overexpression has been reported in several tumors, such as increases during cell cycle progression to G2 phase. Cyclin A canine mammary tumors [12, 17, 34] and, canine and feline is overexpressed in some hepatocellular carcinomas because it squamous cell carcinomas [12, 40]. lacks a cyclin destruction box due to genomic insertion by the There are few data about alterations of cyclin expression in hepatitis B virus [7]. Cyclin A alterations have also recently canine and feline tumors. In this study, immunohistochemical been identified in several tumors including squamous cell car- analysis for cyclin A, cyclin D1 and p53 expression in mam- cinomas of the lung [9, 44–46], oral cavity [22], esophagus mary tumors, squamous cell carcinomas and basal cell tumors [11] and uterine cervix [20]. of dogs and cats was performed in order to clarify whether The D-type cyclins act primarily by regulating the activity overexpression of these gene products correlates with canine of cdk4/cdk6 in the G1 phase of the cell cycle. In human, and feline tumorigenesis. cyclin D1, also known as PRAD-1 or bcl-1, is a 36 kDa pro- tein and the cyclin D1 gene is located on 11q13. Maximum MATERIALS AND METHODS expression of cyclin D1 occurs at a critical point in mid to late Tissue samples: A total of 176 cases were obtained from surgical specimens between 1996 and 1998 at the Department *CORRESPONDENCE TO: TATEYAMA, S., Department of Veteri- of Veterinary Pathology, Miyazaki University, Japan. For his- nary Pathology, Faculty of Agriculture, Miyazaki Univer- topathology, the specimens were fixed in 10% neutral buff- sity, Miyazaki 889–2192, Japan. 744 Y. MURAKAMI ET AL. Table 1. Histological typing of 176 cases examined ated types. Twenty feline squamous cell carcinomas were also Species Histological type Number of cases graded as 5 well differentiated types, 8 common types, 5 poorly differentiated types and 2 cases of Bowen’s disease. Dog 108 Antibody: The primary antibodies used were a rabbit poly- Mammary 75 Adenosis 2 clonal antibody against human cyclin A, a recombinant pro- Benign tumor 35 tein corresponding to amino acids 1–432 representing full- Adenoma 25 length cyclin A of human origin (H-432, Santa Cruz Biotech, Benign mixed tumor 10 U.S.A.), a rabbit polyclonal antibody against human cyclin Malignant tumor 38 D1, a recombinant protein corresponding to amino acids 1- Adenocarcinoma 33 295 representing full-length cyclin D1 of human origin (H- Malignant mixed tumor 3 Malignant myoepithelioma 2 295, Santa Cruz Biotech, U.S.A.) and a rabbit polyclonal anti- Squamous cell carcinoma 16 body against human p53 antibody, recognizing the wild-type Well differentiated type 5 and mutant forms of p53 (CM1, Novocastra, UK). Common type 5 Immunohistochemistry: Immunohistochemistry was per- Poorly differentiated type 6 formed using an Envision polymer reagent (DAKO, Kyoto, Basal cell tumor 17 Japan). Hydrated autoclave treatment was performed on the Cat 68 Mammary 43 paraffin sections before immunostaining. Endogenous perox- Adenosis 4 idase was quenched by 0.3% hydrogen peroxide in methanol Fibroadenoma 2 for 30 min at room temperature. The sections were incubated Carcinoma 37 with 3% (w/v) bovine serum albumin in PBS for 1 hr at 37°C. Well differentiated type 10 Primary antibodies against cyclin A (1:40), cyclin D1 (1:40) Common type 11 and p53 (1:100) were applied. The sections were incubated Poorly differentiated type 16 with these primary antibodies overnight at 4°C and with Envi- Squamous cell carcinoma 20 Well differentiated type 5 sion polymer reagent for 30 min at 37°C. The chromogenic Common type 8 reaction was carried out with 3,3-diaminobenzidine-4 HCl Poorly differentiated type 5 (0.5 mg/ml) in Tris-hydrochloride buffer, pH 7.6, supple- Bowen’s disease 2 mented with 0.03% (v/v) hydrogen peroxide and counter- Basal cell tumor 5 stained with Mayer’s hematoxylin. Total 176 Microscopic evaluation: The immunoreactivities for cyclin A, cyclin D1 and p53 were assessed using a grading system based on the percentage of positive nuclei. The stain- ered formalin, cut at a thickness of 4 µm and stained with ing was scored as 0, tumor with no nuclear staining; 1, tumor hematoxylin and eosin (HE) for light microscopy. The patho- with <10% of its nuclei stained; 2, tumor with 10–50% of its logic characteristics of 176 cases are listed in Table 1. One nuclei stained; 3, tumor with >50% of its nuclei stained. Spec- hundred and seventy-six cases comprised 108 canine cases (75 imens assigned scores of 2 to 3 were considered positive. mammary lesions, 16 squamous cell carcinomas and 17 basal cell tumors) and 68 feline cases (43 mammary lesions, 20 RESULTS squamous cell carcinomas and 5 basal cell tumors). Both canine and feline squamous cell carcinomas were restricted to The immunohistochemical data for expression for cyclin A, the cases of origin of skin. The 75 canine mammary lesions cyclin D1 and p53 are summarized in Tables 2 and 3, and the were divided into 3 groups comprising 2 adenosis, 35 benign details are described below. tumors (25 adenomas and 10 benign mixed tumors) and 38 Cyclin A: Nuclear staining of cyclin A was observed in 19/ malignant tumors (33 adenocarcinomas, 3 malignant mixed 75 (25.3%) canine mammary lesions, 18/43 (41.9%) feline tumors and 2 malignant myoepitheliomas). The 43 feline mammary lesions, 7/16 (43.8%) canine squamous cell carci- mammary lesions included 4 adenosis, 2 fibroadenomas, and nomas, 18/20 (90%) feline squamous cell carcinomas and 3/ 37 feline mammary carcinomas. The grade for feline mam- 17 (17.6%) canine basal cell tumors, but was not seen in feline mary carcinomas was derived from the assessment of three basal cell tumors. Among the malignant mammary tumors, morphological features: degree of tubule formation, degree of 19/38 (50%) canine malignant tumors and 18/37 (48.6%) nuclear and cellular pleomorphism and mitotic activity.
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