The human ERBB2 proto-oncogene is widely considered a key gene involved in human breast cancer onset and progression. Among spontaneous tumors, mammary tumors are the most frequent cause of cancer death in cats and second most frequent in humans. In fact, naturally occurring tumors in domestic animals, more particularly cat mammary tumors, have been proposed as a good model for human breast cancer, but critical genetic and molecular information is still scarce. The aims of this study include the analysis of the cat ERBB2 gene partial sequences (between exon 17 and 20) in order to characterize a normal and a mammary lesion heterogeneous populations. Cat genomic DNA was extracted from normal frozen samples ( n = 16) and from frozen and formalin-fixed paraffin-embedded mammary lesion samples ( n = 41). We amplified and sequenced two cat ERBB2 DNA fragments comprising exons 17 to 20. It was possible to identify five sequence variants and six haplotypes in the total population. Two sequence variants and two haplotypes show to be specific for cat mammary tumor samples. Bioinformatics analysis predicts that four of the sequence variants can produce alternative transcripts or activate cryptic splicing sites. Also, a possible association was identified between clinicopathological traits and the variant haplotypes. As far as we know, this is the first attempt to examine ERBB2 genetic variations in cat mammary genome and its possible association with the onset and progression of cat mammary tumors. The demonstration of a possible association between primary tumor size (one of the two most important prognostic factors) and the number of masses with the cat ERBB2 variant haplotypes reveal the importance of the analysis of this gene in veterinary medicine.
References
[1]
MacEwen, E.G. Spontaneous tumors in dogs and cats: Models for the study of cancer biology and treatment. Cancer Metastasis Rev 1990, 9, 125–136.
[2]
Vail, D.M.; MacEwen, E.G. Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest 2000, 18, 781–792.
[3]
Zappulli, V.; de Zan, G.; Cardazzo, B.; Bargelloni, L.; Castagnaro, M. Feline mammary tumors in comparative oncology. J. Dairy Res 2005, 72, 98–106.
[4]
Weijer, K.; Hart, A.A.M. Prognostic Factors in feline mammary carcinoma. J. Natl. Cancer Inst 1983, 70, 709–716.
[5]
Hahn, K.A.; Bravo, L.; Avenell, J.S. Feline breast carcinoma as a pathologic and therapeutic model for human breast cancer. In Vivo 1994, 8, 825–828.
[6]
de Maria, R.; Olivero, M.; Iussich, S.; Nakaichi, M.; Murata, T.; Biolatti, B.; di Renzo, M.F. Spontaneous feline mammary carcinoma is a model of HER2 overexpressing poor prognosis human breast cancer. Cancer Res 2005, 65, 907–912.
[7]
Burrai, G.P.; Mohammed, S.I.; Miller, M.A.; Marras, V.; Pirino, S.; Addis, M.F.; Uzzau, S.; Antuofermo, E. Spontaneous feline mammary intraepithelial lesions as a model for human estrogen receptor- and progesterone receptor-negative breast lesions. BMC Cancer 2010, 10, doi:10.1186/1471-2407-10-156.
[8]
Lana, S.E.; Rutteman, G.R.; Withrow, S.J. Tumors of the Mammary Gland. In Small Animal Clinical Oncology, 4th ed; Withrow, S.J., Vail, D.M., Eds.; Saunders Elsevier: Toronto, Canada, 2001; pp. 628–636.
[9]
Gimenez, F.; Hecht, S.; Craig, L.E.; Legendre, A.M. Early detection, aggressive therapy. Optimizing the management of feline mammary masses. J. Feline Med. Surg 2010, 12, 214–224.
[10]
Owen, L.N. Classification of Tumors in Domestic Animals, 1st ed ed.; World Health Organization: Geneva, Belgium, 1980.
[11]
Ito, T.; Kadosawa, T.; Mochizuki, M.; Matsunaga, S.; Nishimura, R.; Sasaki, N. Prognosis of malignant mammary tumors in 53 cats. J. Vet. Med. Sci 1996, 58, 723–726.
Ross, J.S.; Slodkowska, E.A.; Symmans, W.F.; Pusztai, L.; Ravnin, P.M.; Hortobagyi, G.N. The erbB-2 receptor and breast cancer: Ten years of targeted anti-erbB-2 therapy and personalized medicine. Oncologist 2009, 14, 320–368.
[14]
Tao, W.; Wang, C.; Han, R.; Jiang, H. HER2 codon 655 polymorphism and breast cancer risk: A meta-analysis. Breast Cancer Res. Treat 2009, 114, 371–376.
Benusiglio, P.R. Focus on ERBB2. Pharmaogenomics 2007, 9, 825–828.
[17]
Slamon, D.J.; Godolphin, W.; Jones, L.A.; Holt, J.A.; Wong, S.G.; Keith, D.E.; Levin, W.J.; Stuart, S.G.; Udove, J.; Ullrich, A.; et al. Studies of the erbB-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989, 244, 707–712.
[18]
Kolibaba, K.S.; Druker, B.J. Protein tyrosine kinases and cancer. Biochim. Biophys. Acta 1997, 1333, 217–248.
[19]
Ordás, J.; Millán, Y.; Dios, R.; Reymundo, C.; de las Mulas, J.M. Proto-oncogene erbB-2 in normal, dysplastic and tumorous feline mammary glands: An immunohistochemical and chromogenic in situ hybridization study. BMC Cancer 2007, 7, doi:10.1186/1471-2407-7-179.
Borg, A.; Tandon, A.K.; Sigurdsson, H.; Clark, G.M.; Fern？, M.; Fuqua, S.A.W.; Killander, D.; McGuire, W.L. erbB-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res 1990, 50, 4332–4337.
[22]
Charpin, C.; Garcia, S.; Bouvier, C.; Martini, F.; Lavaut, M.N.; Allasia, C.; Bonnier, P.; Andrac, L. c-erbB-2 oncoprotein detected by automated quantitative immunocytochemistry in breast carcinomas correlates with patients’ overall and disease-free survival. Br. J. Cancer 1997, 75, 1667–1673.
Leary, R.J.; Lin, J.C.; Cummins, J.; Boca, S.; Wood, L.D.; Parsons, D.W.; Jones, S.; Sj？blom, T.; Park, B.H.; Parsons, R.; et al. Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proc. Natl. Acad. Sci. USA 2008, 105, 16224–16229.
[25]
Benusiglio, P.R.; Lesueur, F.; Luccarini, C.; Conroy, D.M.; Shah, M.; Easton, D.F.; Day, N.E.; Dunning, A.M.; Pharoah, P.D.; Ponder, B.A. Common ERBB2 polymorphisms and risk of breast cancer in a white British population: A case-control study. Breast Cancer Res 2005, 7, 204–209.
[26]
Han, W.; Kang, D.; Lee, J.E.; Park, I.A.; Choi, J.Y.; Lee, K.M.; Bae, J.Y.; Kim, S.; Shin, E.S.; Lee, J.E.; et al. A haplotype analysis of erbB-2 gene polymorphisms: Association with breast cancer risk, erbB-2 protein expression in the tumor, and disease recurrence in Korea. Clin. Cancer Res 2005, 11, 4775–4778.
[27]
Breyer, J.P.; Sanders, M.E.; Airey, D.C.; Cai, Q.; Yaspan, B.L.; Schuyler, P.A.; Dai, Q.; Boulos, F.; Olivares, M.G.; Bradley, K.M.; et al. Heritable variation of ERBB2 and breast cancer risk. Cancer Epidemiol. Biomarkers Prev 2009, 18, 1252–1258.
[28]
Desmet, F.O.; Hamroun, D.; Lalande, M.; Collod-Béroud, G.; Claustres, M.; Béroud, C. Human splicing finder: An online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009, 37, doi:10.1093/nar/gkp215.
[29]
Mayr, B.; Schaffner, G.; Kurzbauer, R.; Reifinger, M.; Schellander, K. Sequence of an exon of tumor suppressor p53 gene—A comparative study in domestic animals: Mutation in a feline solid mammary carcinoma. Br. Vet. J 1995, 151, 325–329.
[30]
Mayr, B.; Reifinger, M.; Alton, K.; Schaffner, G. Novel p53 tumor suppressor mutations in cases of spindle cell sarcoma, pleomorphic sarcoma and fibrosarcoma in cats. Vet. Res. Commun 1998, 22, 249–255.
[31]
Mayr, B.; Blauensteiner, J.; Edlinger, A.; Reifinger, M.; Alton, K.; Schaffner, G.; Brem, G. Presence of p53 mutations in feline neoplasms. Res. Vet. Sci 2000, 68, 63–70.
[32]
Baptista, C.S.; Santos, S.; Laso, A.; Bastos, E.; ávila, S.; Guedes-Pinto, H.; G？rtner, F.; Gut, I.G.; Castrillo, J.L.; Chaves, R. Sequence variation and mRNA expression of the TWIST1 gene in cats with mammary hyperplasia and neoplasia. Vet. J 2011, 191, 203–207.
[33]
Nelson, S.E.; Gould, M.N.; Hampton, J.M. A case-control study of the HER2 Ile655Val polymorphism in relation to risk of invasive breast cancer. Breast Cancer Res 2005, 7, R357–R364.
[34]
Beauclair, S.; Formento, P.; Fischel, J.L.; Lescaut, W.; Largillier, R.; Chamorey, E.; Hofman, P.; Ferrero, J.M.; Pagès, G.; Milano, G. Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity. Ann. Oncol 2007, 18, 1335–1341.
[35]
Puputti, M.; Sihto, H.; Isola, J.; Butzow, R.; Joensuu, H.; Nupponen, N.N. Allelic imbalance of HER2 variant in sporadic breast and ovarian cancer. Cancer Genet. Cytogenet 2006, 167, 32–38.
[36]
Jo, U.H.; Han, S.G.L.; Seo, J.H.; Park, K.H.; Lee, J.W.; Lee, H.J.; Ryu, J.S.; Kim, Y.H. The genetic polymorphisms of HER-2 and the risk of lung cancer in a Korean population. BMC Cancer 2008, 8, doi:10.1186/1471-2407-8-359.
[37]
Fleishman, S.J.; Schlessinger, J.; Ben-Tal, N. A putative molecular-activation switch in the transmembrane domain of ERBB2. Proc. Natl. Acad. Sci. USA 2002, 99, 15937–15940.
[38]
Bennasroune, A.; Fickova, M.; Gardin, A.; Dirrig-Grosch, S.; Aunis, D.; Cremel, G.; Hubert, P. Transmembrane peptides as inhibitors of ErbB receptor signaling. Mol. Biol. Cell 2004, 15, 3464–3474.
[39]
Lengauer, C.; Kinzler, K.W.; Vogelstein, B. Genetic instabilities in human cancers. Nature 1998, 396, 643–649.
[40]
Hartwell, L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 1992, 71, 543–546.
[41]
Bauer-Mehren, A.; Furlong, L.I.; Rautschka, M.; Sanz, F. From SNPs to pathways: Integration of functional effect of sequence variations on models of cell signaling pathways. BMC Bioinform 2009, 10, doi:10.1186/1471-2105-10-S8-S6.
[42]
Venables, J.P. Aberrant and alternative splicing in cancer. Cancer Res 2004, 64, 7647–7654.
[43]
Loretti, A.P.; Ilha, M.R.; Ordas, J.; Martin de las Mulas, J. Clinical, pathological and immunohistochemical study of feline mammary fibro epithelial hyperplasia following a single injection of depot medroxyprogesterone acetate. J. Feline Med. Surg 2005, 7, 43–52.
[44]
Rutteman, G.R.; Misdorp, W. Hormonal background of canine and feline mammary tumors. J. Reprod. Fertil. Suppl 1993, 47, 483–487.
[45]
Hahn, K.A.; Bravo, L.; Avenell, J.S. Feline breast carcinoma as a pathologic and therapeutic model for human breast cancer. In Vivo 1994, 8, 825–828.
[46]
Hampe, J.F.; Misdorp, W. Tumours and dysplasias of the mammary gland. Bull. World Health Organ 1974, 50, 111–133.
[47]
MacEwen, E.G.; Hayes, A.A.; Harvey, H.J.; Patnaik, A.K.; Mooney, S.; Passe, S. Prognostic factors for feline mammary tumors. J. Am. Vet. Med. Assoc 1984, 2, 201–204.
[48]
Viste, J.R.; Myers, S.L.; Singh, B.; Simko, E. Feline mammary adenocarcinoma: Tumor size as a prognostic indicator. Can. Vet. J 2002, 43, 33–37.
[49]
Misdorp, W.; Else, R.W.; Helmén, E.; Lipscomb, T.P. Histological Classification of Mammary Tumors of the Dog and Cat; Armed Forces Institute of Pathology and World Health Organization: Washington, DC, USA, 1999.
[50]
Santos, S.; Sá, D.; Bastos, E.; Guedes-Pinto, H.; Gut, I.; G？rtner, F.; Chaves, R. An efficient protocol for genomic DNA extraction from formalin-fixed paraffin-embedded tissues. Res. Vet. Sci 2009, 86, 421–426.
[51]
den Dunnen, J.T.; Antonarakis, S.E. Mutation nomenclature extensions and suggestions to describe complex mutations: A Discussion. Hum. Mutat 2000, 15, 7–12.
[52]
den Dunnen, J.T.; Antonarakis, S.E. Nomenclature for the description of human sequence variations. Hum Genet 2001, 109, 121–124.
[53]
Ogino, S.; Gulley, M.L.; den Dunnen, J.T.; Wilson, R.B. Association for molecular pathology training and education committee. Standard mutation nomenclature in molecular diagnostics. practical and educational challenges. J. Mol. Diagn 2007, 9, 1–6.
[54]
Tommasi, S.; Fedele, V.; Lacalamita, R.; Crapolicchioa, A.; Perlinob, E.; Bellizia, A.; Paradiso, A. Molecular and functional characteristics of ERBB2 in normal and cancer breast cells. Cancer Lett 2004, 209, 215–222.
