Current invasive and non-invasive biomarkers in canine mammary tumors

Yıl 2021, , 39 - 56, 30.04.2021

Aslihan Baykal , Özge Turna

https://doi.org/10.30704/http-www-jivs-net.892668

Öz

In bitches, the incidence of mammary tumors is determined at %50 of all neoplasms. Most of the cases are malignant and tend to metastasize. Because of this, early diagnosis has an important value. Due to the molecular and clinical similarities of canine mammary tumors to human breast cancers, human breast cancer markers are also detectable in cases of canine mammary tumors. Generally, biomarkers provide information about criteria such as clinical diagnosis, early diagnosis, prognosis, and determination of the treatment protocol. When choosing the appropriate biomarker, it should be taken into account that it is easy to apply, has a positive correlation with tumor specificity and malignancy, and whether gives precise information about prognosis. Due to the heterogeneous nature of canine mammary tumors, an ideal biomarker has not determined yet. However, new studies have revealed the existence of many biomarkers. In this review it is given to qualified and current biomarkers can be used in dogs, including invasive and non-invasive mammary tumor biomarkers.

Anahtar Kelimeler

biomarkers, dogs, mammary neoplasms

Kaynakça

• 1. Alenza, M. P., Pena, L., Castillo, N. D., & Nieto, A. I. (2000). Factors influencing the incidence and prognosis of canine mammary tumours. Journal of Small Animal Practice, 41 (7), 287-291.
• 2. Almeida, J. R. C., Pedrosa, N. L., Leite, J. B., Fleming, T. R., Carvalho, V. H., & Cardoso, A. A. (2007). Tumor markers: A literature review. Revista Brasileira de Cancerologia, 53 (3), 305-316.
• 3. Andrews, J. L., Kim, A. C., & Hens, J. R. (2012). The role and function of cadherins in the mammary gland. Breast Cancer Research, 14 (1), 1-10.
• 4. Araújo, M. R., Campos, L. C., Damasceno, K. A., Gamba, C. O., Ferreira, E., & Cassali, G. D. (2016). HER-2, EGFR, Cox-2 and Ki67 expression in lymph node metastasis of canine mammary carcinomas: association with clinical-pathological parameters and overall survival. Research in Veterinary Science, 106, 121-130.
• 5. Asproni, P., Ressel, L., Millanta, F., Vannozzi, I., & Poli, A. (2015). Co-localization of PTEN and E-cadherin in canine mammary hyperplasias and benign and malignant mammary tumors. Research in Veterinary Science, 103, 113-118.
• 6. Bakthisaran, R., Tangirala, R., & Rao, C. M. (2015). Small heat shock proteins: role in cellular functions and pathology. Biochimica et Biophysica Acta Molecular Cell Reserach, 1854 (4), 291-319.
• 7. Baranwal, S., & Alahari, S. K. (2009). Molecular mechanisms controlling E-cadherin expression in breast cancer. Biochemical and Biophysical Research Communications, 384 (1), 6-11.
• 8. Benavente, M. A., Bianchi, C. P., & Aba, M. A. (2016). Canine mammary tumors: risk factors, prognosis and treatments. Journal of Animal and Veterinary Advances, 6 (8), 1291-1300.
• 9. Beauvais, W., Cardwell, J. M., & Brodbelt, D. C. (2012). The effect of neutering on the risk of mammary tumours in dogs–a systematic review. The Journal of Small Animal Practice, 53 (6), 314-322.
• 10. Ben-Baruch, A. (2002). Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor–microenvironment interactions. Breast Cancer Research, 5 (1), 31.
• 11. Benavente, M. A., Bianchi, C. P., & Aba, M. A. (2019). Expression of oxytocin receptors in canine mammary tumours. Journal of Comparative Pathology, 170, 26-33.
• 12. Benavente, M. A., Bianchi, C. P., Imperiale, F., & Aba, M. A. (2016). Antiproliferative effects of oxytocin and desmopressin on canine mammary cancer cells. Frontiers in Veterinary Science, 3 (2), 119.
• 13. Bergman, I. (2012). The significance of oxytocin in canine mammary tumours. Master thesis, Swedish University, Uppsala.
• 14. Boggs, R. M., Wright, Z. M., Stickney, M. J., Porter, W. W., & Murphy, K. E. (2008). MicroRNA expression in canine mammary cancer. Mammalian Genome. 19 (7-8), 561-569.
• 15. Boller, K., Vestweber, D., & Kemler, R. (1985). Cell-adhesion molecule uvomorulin is localized in the intermediate junctions of adult intestinal epithelial cells. The Journal of Cell Biology, 100 (1), 327-332.
• 16. Borgoño, C. A., & Diamandis, E. P. (2004). The emerging roles of human tissue kallikreins in cancer. Nature Reviews Cancer, 4 (11), 876-890.
• 17. Bravo, R., & Celis, J. E. (1980). A search for differential polypeptide synthesis throughout the cell cycle of HeLa cells. The Journal of Cell Biology, 84 (3), 795-802.
• 18. Brunetti, B., Sarli, G., Preziosi, R., Leprotti, S., & Benazzi, C. (2003). E‐cadherin expression in canine mammary carcinomas with regional lymph node metastases. Journal of Veterinary Medicine. A Physiology, Pathology, Clinical Medicine, 50 (10), 496-500.
• 19. Bulkowska, M., Rybicka, A., Senses, K. M., Ulewicz, K., Witt, K., Szymanska, J., … & Krol, M. (2017). MicroRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours. BioMed Central Cancer, 17 (1), 728.
• 20. Campos, L. C., Lavalle, G. E., Estrela‐Lima, A., Melgaço de Faria, J. C., Guimarães, J. E., Dutra, A. P., … & Cassali, G. D. (2012). CA 15.3, CEA and LDH in dogs with malignant mammary tumors. Journal of Veterinary Internal Medicine, 26 (6), 1383-1388.
• 21. Canadas-Sousa, A., Santos, M., Leal, B., Medeiros, R., & Dias-Pereira, P. (2019). Estrogen receptors genotypes and canine mammary neoplasia. BioMed Central Veterinary Research, 15 (1), 325.
• 22. Cardoso, F., Saghatchian, M., & Thompson, A. (2008). Inconsistent criteria used in american society of clinical oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Journal of Clinical Oncology, 26 (12), 2058-2059.
• 23. Carvalho, M. I., Guimarães, M. J., & Pires, I. et al. (2013). EGFR and microvessel density in canine malignant mammary tumours. Research in Veterinary Science, 95 (3), 1094-1099.
• 24. Carvalho, M. I., Pires, I., Prada, J., Lobo, L., & Queiroga, F. L. (2016). Ki-67 and PCNA expression in canine mammary tumors and adjacent nonneoplastic mammary glands: prognostic ımpact by a multivariate survival analysis. Veterinary Pathology, 53 (6), 1138-1146.
• 25. Carvalho, M. I., Pires, I., Prada, J., Pinto, C., Gregorio, H., Cogliati, B. & Queiroga, F. L. (2019). Assessing the ınterleukin 35 ımmunoexpression in malignant canine mammary tumors: association with clinicopathological parameters and prognosis. Anticancer Research, 39 (4), 2077-2083.
• 26. Cassoni, P., Sapino, A., Marrocco, T., Chini, B., & Bussolati, G. (2004). Oxytocin and oxytocin receptors in cancer cells and proliferation. Journal of Neuroendocrinology, 16 (4), 362-364.
• 27. Dantas Cassali, G., Cavalheiro Bertagnolli, A., Ferreira, E., Damasceno K. A., Gamba, C. O., & de Campos, C. B. (2012). Canine mammary mixed tumours: a review. Vet. Med. Int, 48 (1), 117-131.
• 28. Cawthorn, T. R., Moreno, J. C., Dharsee, M., Tran-Thanh, D., Ackloo, S., Hong Zhu, P., … & Done, S. J. (2012). Proteomic analyses reveal high expression of decorin and endoplasmin (HSP90B1) are associated with breast cancer metastasis and decreased survival. Public Library of Science. 7 (2), e30992.
• 29. Celis, J. E., & Celis, A. (1985). Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. Proceedings of the National Academy of Science of the United States of America, 82 (10), 3262-3266.
• 30. Cerón, J. J. (2019). Acute phase proteins, saliva and education in laboratory science: an update and some reflections. BMC Veterinary Research, 15(1), 1-8.
• 31. Chan, K. K., Matchett, K. B., McEnhill, P. M., Dakir, E. H., McMullin, M. F., El-Tanani, Y., … & El-Tanani, M. (2015). Protein deregulation associated with breast cancer metastasis. Cytokine & Growth Factor Reviews, 26 (4), 415-423.
• 32. Chang, C. C., Tsai, M. H., Liao, J. W., Chan, J. P. W., Wong, M. L., & Chang, S. C. (2009). Evaluation of hormone receptor expression for use in predicting survival of female dogs with malignant mammary gland tumors. Journal of American Veterinary Medical Association, 235 (4), 391-396.
• 33. Changkija, B., & Konwar, R. (2012). Role of interleukin-10 in breast cancer. Breast Cancer Research and Treatment, 133 (1), 11-21.
• 34. Chen, Y. C., Chang, S. C., Huang, Y. H., Lee Y. J., Chang, C. C., Liao J. W., & Hsu, W. L. (2019). Expression and the molecular forms of neutrophil gelatinase‐associated lipocalin and matrix metalloproteinase 9 in canine mammary tumours. Veterinary and Comparative Oncology, 17 (3), 427-438.
• 35. Chmielewska-Krzesińska, M., Jakimiuk, A., & Wąsowicz, K. (2019). Stability of αB-crystallin gene expression in canine mammary gland neoplasms. Should it be considered as circulating tumor cell genetic marker?. Polish Journal of Veterinary Science, 22 (3), 523-529.
• 36. Choi, U. S., & Kim, D. Y. (2011). Immunocytochemical detection of Ki‐67 in Diff‐Quik‐stained cytological smears of canine mammary gland tumours. Cytopathology, 22 (2), 115-120.
• 37. Chou, J., Lin, J. H., Brenot, A., Kim, J. W., Provot, S., & Werb, Z. (2013). GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression. Nature Cell Biology, 15 (2), 201-213.
• 38. Collison, L. W., Chaturvedi, V., Henderson, A. L., Giacomin, P. R., Guy, C., Bankoti, J., … & Vignali, D. A. A. (2010). IL-35-mediated induction of a potent regulatory T cell population. Nature Immunology, 11 (12), 1093-1101.
• 39. Da Costa, A., Oliveira, J. T., Gärtner, F., Kohn, B., Gruber, A. D., & Klopfleisch, R. (2011). Potential markers for detection of circulating canine mammary tumor cells in the peripheral blood. The Veterinary Journal, 190 (1), 165-168.
• 40. de Andrés, P. J., Illera, J. C., Cáceres, S., Díez, L., Pérez-Alenza, M. D., & Peña, L. (2013). Increased levels of interleukins 8 and 10 as findings of canine inflammatory mammary cancer. Veterinary Immunology and Immunopathology, 152 (3-4), 245-251.
• 41. De Las Mulas, J. M., Millán, Y., & Dios, R. (2005). A prospective analysis of immunohistochemically determined estrogen receptor α and progesterone receptor expression and host and tumor factors as predictors of disease-free period in mammary tumors of the dog. Veterinary Pathology, 42 (2), 200-212.
• 42. Degterev, A., Boyce, M., & Yuan, J. (2003). A decade of caspases. Oncogene, 22 (53), 8543-8567.
• 43. Deocaris, C. C., Kaul, S. C., & Wadhwa, R. (2006). On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones, 11 (2), 116.
• 44. Dolka, I., Król, M., & Sapierzyński, R. (2016). Evaluation of apoptosis-associated protein (Bcl-2, Bax, cleaved caspase-3 and p53) expression in canine mammary tumors: An immunohistochemical and prognostic study. Research in Veterinary Science, 105, 124-133.
• 45. Dutra, A. P., Granja, N. V. M., Schmitt, F. C., & Cassali, G. D. (2004). c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors. Brazilian Journal of Medical and Biological Research, 37 (11), 1673-1681.
• 46. Ellis, R. J., Van der Vies, S. M. (1991). Molecular chaperones. Annual Review of Biochemistry, 60 (1), 321-347.
• 47. Endl, E., Kausch, I., Baack, M., Knippers, R., Gerdes, J., & Scholzen, T. (2001). The expression of Ki‐67, MCM3, and p27 defines distinct subsets of proliferating, resting, and differentiated cells. The Journal of Pathology, 195 (4), 457-462.
• 48. Estrela‐Lima, A., Araújo, M. S. S., Soares, R. P., Ribeiro, L. G. R., Damasceno, K. A., Costa, A. T., … & Cassali, G. D. (2016). Plasma Biomarkers Profile of female dogs with mammary carcinoma and its association with clinical and pathological features. Veterinary and Comparative Oncology, 14 (1), 88-100.
• 49. Fernandes, J. V., Cobucci, R. N.O., Jatobá, C. A. N., de Medeiros Fernandes, T. A. A., de Azevedo, J. W. V., & de Araújo, J. M. G. (2015). The role of the mediators of inflammation in cancer development. Pathology & Oncology Research, 21 (3), 527-534.
• 50. Fernández, C. A., Yan, L, Louis, G., Yang, J., Kutok, J. L., & Moses, M. A. (2005). The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clinical Cancer Research, 11 (15), 5390-5395.
• 51. Franco-Martínez, L., Gelemanović, A., Horvatić, A., Contreras-Agullar, M. D., Dabrowski, R., Mrijak, V., … & Tvarijonaviciute, A. (2020). Changes in Serum and Salivary Proteins in Canine Mammary Tumors. Animals, 10 (4), 741.
• 52. Franco-Martínez, L., Horvatić, A., Gelemanović, A., Samardzija, M., Mrljak, V., Contreras-Aguilar, M. D., … & Tvarijonaviciute, A. (2020). Changes in the salivary proteome associated with canine pyometra. Frontiers in Veterinary Science, 7, 277.
• 53. Ferreira, E., Bertagnolli, A. C., Cavalcanti, M. F., Schmitt, F. C., & Cassali, G. D. (2009). The relationship between tumour size and expression of prognostic markers in benign and malignant canine mammary tumours. Veterinary and Comparative Oncology, 7 (4), 230-235.
• 54. Gama, A., Alves, A., & Schmitt, F. (2008). Identification of molecular phenotypes in canine mammary carcinomas with clinical implications: application of the human classification. Virchows Archiv, 453 (2), 123-132.
• 55. Gama, A., Gärtner, F., Alves, A., & Schmitt, F. (2009). Immunohistochemical expression of Epidermal Growth Factor Receptor (EGFR) in canine mammary tissues. Research in Veterinary Science, 87 (3), 432-437.
• 56. Gama, A., Paredes, J., Gärtner, F., Alves, A., & Schmitt, F. (2008). Expression of E-cadherin, P-cadherin and β-catenin in canine malignant mammary tumours in relation to clinicopathological parameters, proliferation and survival. The Journal of Veterinary Science, 177 (1), 45-53.
• 57. Gasco, M., Shami, S., & Crook, T. (2002). The p53 pathway in breast cancer. Breast Cancer Research, 4 (2), 70.
• 58. Geddes, D. T. (2007). Inside the lactating breast: the latest anatomy research. Journal of Midwifery & Women’s Health, 52 (6), 556-563.
• 59. Gialeli, C., Theocharis, A. D., Karamanos, N. K. (2011). Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. The FEBS Journal, 278 (1), 16-27.
• 60. Giri, K., Mehta, A., & Ambatipudi, K. (2019). In search of the altering salivary proteome in metastatic breast and ovarian cancers. The FASEB Journal. 1 (3), 191-207. 61. Goldschmidt, M., Peña, L., Rasotto, R., & Zappulli, V. (2011). Classification and grading of canine mammary tumors. Veterinary Pathology, 48 (1), 117-131.
• 62. Goplen, D., Bougnaud, S., Rajcevic, U. Bøe, S. O., Skaftnesmo, K. O., Voges, J., … & Bjerkvig, R. (2010). αB-crystallin is elevated in highly infiltrative apoptosis-resistant glioblastoma cells. The American Journal of Pathology, 177 (4), 1618-1628.
• 63. Grösch, S., Maier, T. J., Schiffmann, S., & Geisslinger, G. (2006). Cyclooxygenase-2 (COX-2) independent anticarcinogenic effects of selective COX-2 inhibitors. Journal of the National Cancer Institute, 98 (11), 736-747.
• 64. Guimarães, M. J., Carvalho, M. I., Pires, I., Prada, J., Gil Gonzalez, A., Lopes, C., & Queiroga, F. L. (2014). Concurrent expression of cyclo-oxygenase-2 and epidermal growth factor receptor in canine malignant mammary tumours. Journal of Comparative Pathology, 150 (1), 27-34.
• 65. Hadjiloucas, I., Gilmore, A. P., Bundred, N. J., & Streuli, C. H. (2001). Assessment of apoptosis in human breast tissue using an antibody against the active form of caspase 3: relation to tumour histopathological characteristics. British Journal of Cancer, 85 (10), 1522-1526.
• 66. Hamidinia, M., Boroujerdnia, M. G., Talaiezadeh, A., Solgi, G., Roshani, R., Iranprast, S., & Khodadadi, A. (2015). Increased P-35, EBI3 transcripts and other treg markers in peripheral blood mononuclear cells of breast cancer patients with different clinical stages. Advanced Pharmaceutical Bulletin, 5 (2), 261.
• 67. Hao, S., Chen, X., Wang, F., Shao, Q., Liu, J., Zhao, H., … & Mao, H. (2018). Breast cancer cell–derived IL-35 promotes tumor progression via induction of IL-35-producing induced regulatory T cells. Carcinogenesis, 39 (12), 1488-1496.
• 68. Harris, L., Fritsche, H., Mennel, R., Norton, L., Ravdin, P., Somerfield, S. T. R., … (2007). American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Journal of Clinical Oncology, 25 (33), 5287-5312.
• 69. Hayes, D. F., Sekine, H., Ohno, T., Abe, M., Keefe, K., & Kufe, D. W. (1985). Use of a murine monoclonal antibody for detection of circulating plasma DF3 antigen levels in breast cancer patients. Journal of Clinical Investigation, 75 (5), 1671-1678.
• 70. Heimann, R., Lan, F., McBride, R., & Hellman, S. (2000). Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin. Cancer Research, 60 (2), 298-304.
• 71. HellmÉn, E. (1992). Characterization of four in vitro established canine mammary carcinoma and one atypical benign mixed tumor cell lines. In Vitro Cellular & Developmental Biology Animal, 28 (5), 309-319.
• 72. Heng, B., Lim, C. K., Lovejoy, D. B., Bessede, A., Gluch, L., Guillemin, G. J. (2016). Understanding the role of the kynurenine pathway in human breast cancer immunobiology. Oncotarget, 7 (6), 6506.
• 73. Hsu, W. L., Huang, H. M., Liao, J. W., Wong, M. L., & Chang, S. C. (2009). Increased survival in dogs with malignant mammary tumours overexpressing HER-2 protein and detection of a silent single nucleotide polymorphism in the canine HER-2 gene. Journal of Veterinary Science, 180 (1), 116-123.
• 74. Huang, C., Wang, X., Sun, B., Li, M., Zhao, X., Gu, Y., … & Li, Y. (2015). Study on mouse model of triple-negative breast cancer: association between higher parity and triple-negative breast cancer. Target Oncology, 10 (1), 85-97.
• 75. Hugo, H. J., Saunders, C., Ramsay, R. G., Thompson, E. W. (2015). New insights on COX-2 in chronic inflammation driving breast cancer growth and metastasis. Journal of Mammary Gland Biology and Neoplasia, 20 (3-4), 109-119.
• 76. Ikeda, E., Achen, M. G., Breier, G., & Risau, W. (1995). Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. Journal of Biological Chemistry, 270 (34), 19761-19766.
• 77. Iorio, M. V., Ferracin, M., Liu, C. G., Veronese, A., Spizzo, R., Sabbioni, S., … & Croce, C. M. (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Research, 65 (16), 7065-7070.
• 78. Jose, J., Tavares, C. D., Ebelt, N. D., Lodi, A., Edupuganti, R., Xie, X., … & Dalby, K. N. (2017). Serotonin analogues as inhibitors of breast cancer cell growth. ACS Medicinal Chemistry Letters, 8 (10), 1072-1076.
• 79. Jurikova, M., Danihel, Ľ., Polák, Š., Varga, I. (2016). Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. Acta Histochemica, 118 (5), 544-552.
• 80. Kaszak, I., Ruszczak, A., Kanafa, S., Kacprzak, K., Król, M., & Jurka, P. (2018). Current biomarkers of canine mammary tumors. Acta Veterinaria Scandinavica, 60 (1), 1-13.
• 81. Kausitz, J., Altaner, C., Boljesikova, E., & Spanik, S. (2003). Tumor markers (Nadorove markery). In: Oncology (Onkologia), VEDA, eds., Bratislava, Slovenskej ´ akademie vied. 119–124.
• 82. Kim, J. H., Yu, C. H., Yhee, J. Y., Im, K. S., & Sur, J. H. (2010). Lymphocyte infiltration, expression of interleukin (IL)-1, IL-6 and expression of mutated breast cancer susceptibility gene-1 correlate with malignancy of canine mammary tumours. Journal of Comparative Pathology, 142 (2-3), 177-186.
• 83. Kjeldsen, L., Cowland, J. B., & Borregaard, N. (2000). Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse. Biochimica et Biophysica Acta, 1482 (1-2), 272-283.
• 84. Knottenbelt, C., Chambers, G., Gault, E., & Argyle, D. J. (2006). The in vitro effects of piroxicam and meloxicam on canine cell lines. Journal of Small Animal Practice, 47 (1), 14-20.
• 85. Kumar, B. S., Bhardwaj, R., Mahajan, K., Kashyap, N., Kumar, A., & Verma, R. (2018). The overexpression of Hsp90B1 is associated with tumorigenesis of canine mammary glands. Molecular and Cellular Biochemistry, 440 (1-2), 23-31.
• 86. Kymionis, G. D., Dimitrakakis, C. E., Konstadoulakis, M. M., Arzimanoglou, I., Leandros, E., Chalkiadakis, G., … & Michalas, S. (2001). Can expression of apoptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients?. Journal of Surgical Research, 99 (2), 161-168.
• 87. Lana, S. E., Rutteman, G. R., & Withrow, S. J (2007). Tumors of the mammary gland. In: In Withrow & MacEwen's small animal clinical oncology. Withrow SJ, Vail DM (Ed), 619-638, Saunders Elsevier, Missouri.
• 88. Lavalle, G. E., Bertagnolli, A. C., Tavares, W. L. F., & Cassali, G. D. (2009). Cox-2 expression in canine mammary carcinomas: correlation with angiogenesis and overall survival. Veterinary Pathology, 46 (6), 1275-1280.
• 89. Ławicki, S., Zajkowska, M., Głażewska, E. K., Będkowska, G. E., & Szmitkowski, M. (2017). Plasma levels and diagnostic utility of VEGF, MMP-2 and TIMP-2 in the diagnostics of breast cancer patients. Biomarkers, 22 (2), 157-164.
• 90. Ledecky, V., Valencakova-Agyagosova, A., Lepej, J., Frischova, Z., Hornak, S., & Nagy, V. (2013). Determination of carcinoembryonic antigen and cancer antigen values with the radioimmunoassay method in healthy females dogs. Veterinary Medicine-Czech, 58 (5), 277-283.
• 91. Lee, A. S. (2014). Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nature Reviews Cancer, 14 (4), 263-276.
• 92. Lee, C. H., Kim, W. H., Lim, J. H., Kang, M. S., Kim, D. Y., & Kweon, O. K. (2004). Mutation and overexpression of p53 as a prognostic factor in canine mammary tumors. Journal of Veterinary Science, 5 (1), 63-70.
• 93. Liao, K. L., Bai, X. F., & Friedman, A. (2014). Mathematical modeling of Interleukin-35 promoting tumor growth and angiogenesis. Public Library of Science One, 9 (10), e110126.
• 94. Lin, W. W., & Karin, M. (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. Journal of Clinical Investigation, 117 (5), 1175-1183.
• 95. Liu, B., Earl, H. M., Baban, D., Shoaibi, M., Fabra, A., Kerr, D. J., & Seymour, L. W. (1995). Melanoma cell lines express VEGF receptor KDR and respond to exogenously added VEGF. Biochemical and Biophysical Research Communications, 217 (3), 721-727.
• 96. Łopuszyński, W., Szczubiał, M., & Komsta, R. (2010). Prognostic status of p53 protein accumulation in canine malignant mammary tumours. Bulletin of the Veterinary Institute Pulawy, 54, 105-111.
• 97. Löhr, C. V., Teifke, J. P., Failing, K., & Weiss, E. (1997). Characterization of the proliferation state in canine mammary tumors by the standardized AgNOR method with postfixation and immunohistologic detection of Ki-67 and PCNA. Veterinary Pathology, 34 (3), 212-221.
• 98. Lutful Kabir, F. M., DeInnocentes, P., & Bird, R. C. (2015). Altered microRNA expression profiles and regulation of INK4A/CDKN2A tumor suppressor genes in canine breast cancer models. Journal of Cellular Biochemistry, 116 (12), 2956-2969.
• 99. Lüder Ripoli, F., Conradine Hammer, S., Mohr, A., Willenbrock, S., Hewicker-Trautwein, M., Brenig, B., … & Nolte, I. (2016). Multiplex Gene Expression Profiling of 16 Target Genes in Neoplastic and Non-Neoplastic Canine Mammary Tissues Using Branched-DNA Assay. International Journal of Molecular Sciences, 17 (9), 1589.
• 100. Lüftner, D., Lüke, C., & Possinger, K. (2003). Serum HER-2/neu in the management of breast cancer patients. Clinical Biochemistry, 36 (4), 233-240.
• 101. Malin, D., Petrovic, V., Strekalova, E., Sharma, B., & Cryns, V. L. (2016). αB-crystallin: Portrait of a malignant chaperone as a cancer therapeutic target. Pharmacology & Therapeutics, 160, 1-10.
• 102. Malin, D., Strekalova, E., & Petrovic, V. (2014). αB-crystallin: a novel regulator of breast cancer metastasis to the brain. Clinical Cancer Research, 20 (1), 56-67.
• 103. Manuali, E., De Giuseppe, A., & Feliziani, F. (2012). CA 15–3 cell lines and tissue expression in canine mammary cancer and the correlation between serum levels and tumour histological grade. BMC Veterinary Research, 8 (1), 86.
• 104. Martins, G. R., Gelaleti, G. B., Moschetta, M. G., Maschio-Signorini, L. B., Zuccari, D. A., de Campos, P. (2016). Proinflammatory and anti-inflammatory cytokines mediated by NF-κB factor as prognostic markers in mammary tumors. Mediators of Inflammation, 2016.
• 105. Matos, A. J. F., Lopes, C., Carvalheira, J., Santos, M., Rutteman, G. R., & Gärtner, F. (2006). E-cadherin expression in canine malignant mammary tumours: relationship to other clinico-pathological variables. Journal of Comparative Pathology, 134 (2-3), 182-189.
• 106. Merendino, R. A., Arena, A., Capozza, A. B., Chillemi, S., & Mesiti, M. (1996). Serum levels of interleukin-10 in patients affected by breast cancer. Immunology Letters, 53 (1), 59.
• 107. Millanta, F., Calandrella, M., Bari, G., Niccolini, M., Vannozzi, I., & Poli, A. (2005). Comparison of steroid receptor expression in normal, dysplastic, and neoplastic canine and feline mammary tissues. Research in Veterinary Science, 79 (3), 225-232.
• 108. Millanta, F., Citi, S., Della Santa, D., Porciani, M., & Poli, A. (2006). COX-2 expression in canine and feline invasive mammary carcinomas: correlation with clinicopathological features and prognostic fmolecular markers. Breast Cancer Research Treatment, 98 (1), 115-120.
• 109. Molina, R., Barak, V., van Dalen, A., Duffy, M. J., Einarsson, R., Gion, M., … & Stieber, P. (2005). Tumor markers in breast cancer–European Group on Tumor Markers recommendations. Tumor Biology, 26 (6), 281-293.
• 110. Morris, J. S., Dobson, J. M., & Bostock, D. E. (1993). Use of tamoxifen in the control of canine mammary neoplasia. Veterinary Record, 133 (22), 539.
• 111. Muthuswamy, R., Okada, N. J., Jenkins, F. J., McGuire, K., McAuliffe, P. F., Zeh, H. J., … & Kalinski, P. (2017). Epinephrine promotes COX-2-dependent immune suppression in myeloid cells and cancer tissues. Brain, Behavior and Immunity, 62, 78-86.
• 112. Nam, H., Chung, B. C., Kim, Y., Lee, K., & Lee, D. (2009). Combining tissue transcriptomics and urine metabolomics for breast cancer biomarker identification. Bioinformatics, 25 (23), 3151-3157.
• 113. Nami, B., Ghasemi-Dizgah, A., & Vaseghi, A. (2016). Overexpression of molecular chaperons GRP78 and GRP94 in CD44hi/CD24lo breast cancer stem cells. BioImpacts, 6 (2), 105.
• 114. Naz, S., Bashir, M., Ranganathan, P., Bodapati, P., Santosh, V., & Kondaiah, P. (2014). Protumorigenic actions of S100A2 involve regulation of PI3/Akt signaling and functional interaction with Smad3. Carcinogenesis, 35 (1), 14-23.
• 115. Neumann, S., Schuettler, J., Frenz, M., Kaup, F. J., & Gessler, F. (2017). Investigation of serum Ki-67 as a biomarker in tumor-bearing dogs. Research in Veterinary Science, 110, 16-21.
• 116. Newman, G., & Gonzalez-Perez, R. R. (2014). Leptin–cytokine crosstalk in breast cancer. Molecular and Cellular Endocrinology, 382 (1), 570-582.
• 117. Nicolini, A., Carpi, A., & Rossi, G. (2006). Cytokines in breast cancer. Cytokine & Growth Factor Reviews, 17 (5), 325-337.
• 118. Nieto, A., Pena, L., Pérez-Alenza, M. D., Sanchez, M. A., Flores, J. M., & Castano, M. (2000). Immunohistologic detection of estrogen receptor alpha in canine mammary tumors: clinical and pathologic associations and prognostic significance. Veterinary Pathology, 37 (3), 239-247.
• 119. Nieto, A., Perez-Alenza, M. D., Del Castillo, N., Tabanera, E., Castano, M., & Pena, L. (2003). BRCA1 expression in canine mammary dysplasias and tumours: relationship with prognostic variables. Journal of Comparative Pathology, 128 (4), 260-268.
• 120. Nowak, M., Madej, J. A., Pula, B., Dziegiel, P., & Ciaputa, R. (2015). Expression of matrix metalloproteinase 2 (MMP-2), E-cadherin and Ki-67 in metastatic and non-metastatic canine mammary carcinomas. Irish Veterinary Journal, 69 (1), 9.
• 121. O'Day, E., & Lal, A. (2010). MicroRNAs and their target gene networks in breast cancer. Breast Cancer Research, 12 (2), 1-10.
• 122. Olson, B. M., Jankowska-Gan, E., Becker, J. T., Vignali, D. A., Burlingham, W. J., & McNeel, D. G. (2012). Human prostate tumor antigen–specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade. Journal of Immunology, 189 (12), 5590-5601.
• 123. Oto, J., Suzue, A., Inui, D., Fukuta, Y., Hosotsubo, K., Torii, M., … & Nishimura M. (2008). Plasma proinflammatory and anti-inflammatory cytokine and catecholamine concentrations as predictors of neurological outcome in acute stroke patients. Journal of Anesthesia, 22 (3), 207-212.
• 124. Pedersen, K. B., Nesland, J. M., Fodstad, Ø., & Mælandsmo, G. M. (2002). Expression of S100A4, E-cadherin, α-and β-catenin in breast cancer biopsies. British Journal of Cancer, 87 (11), 1281-1286.
• 125. Pena, L. L., Nieto, A. I., Pérez-Alenza, D., Cuesta, P., & Castano, M. (1998). Immunohistochemical detection of Ki-67 and PCNA in canine mammary tumors: relationship to clinical and pathologic variables. Journal of Veterinary Diagnostic Investigation, 10 (3), 237-246.
• 126. Perey, L., Hayes, D. F., Maimonis, P., Abe, M., O'Hara, C., & Kufe, D. W. (1992). Tumor selective reactivity of a monoclonal antibody prepared against a recombinant peptide derived from the DF3 human breast carcinoma-associated antigen. Cancer Research, 52 (9), 2563-2568.
• 127. Plaks, V., Koopman, C. D., & Werb, Z. (2013). Circulating tumor cells. Science, 341 (6151), 1186-1188.
• 128. Platt‐Higgins, A. M., Renshaw, C. A., West, C. R., Winstanley, J. H., De Silva Rudland, S., Barraclough, R., & Rudland, P. S. (2000). Comparison of the metastasis‐inducing protein S100A4 (p9ka) with other prognostic markers in human breast cancer. International Journal of Cancer, 89 (2), 198-208.
• 129. Provatopoulou, X., Gounaris, A., Kalogera, E., Zagouri, F., Flessas, I., Goussetis, E., … & Zografos, G. (2009). Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease. BMC Cancer, 9 (1), 1-7.
• 130. Queiroga, F. L., Pérez‐Alenza, D., González‐Gil, A., Silván, G., Peña, L., & Illera, J. C. (2015). Serum and tissue steroid hormone levels in canine mammary tumours: clinical and prognostic implications. Reproduction in Domestic Animals, 50 (5), 858-865.
• 131. Queiroga, F. L., Perez‐Alenza, M. D., González‐Gil, A., Silván, G., Peña, L., & Illera, J. C. (2017). Quantification of epidermal growth factor receptor (EGFR) in canine mammary tumours by ELISA assay: clinical and prognostic implications. Veterinary and Comparative Oncology, 15 (2), 383-390.
• 132. Queiroga, F. L., Pires, I., Lobo, L., & Lopes, C. S. (2010). The role of Cox-2 expression in the prognosis of dogs with malignant mammary tumours. Research in Veterinary Science, 88 (3), 441-445.
• 133. Queiroga, F. L., Pires, I., Parente, M., Gregório, H., & Lopes, C. S. (2011). COX-2 over-expression correlates with VEGF and tumour angiogenesis in canine mammary cancer. The Veterinary Journal, 189 (1), 77-82.
• 134. Peña, L., Gama, A., Goldschmidt, M. H., Abadie, J., Benazzi, C., Castagnaro, M., … & Martín de las Mulas, J. (2014). Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry. Veterinary Pathology, 51 (1), 127-145.
• 135. Reed, J. C. (2000). Mechanisms of apoptosis. The American Journal of Pathology, 157 (5), 1415-1430.
• 136. Restucci, B., Papparella, S., Maiolino, P., & De Vico, G. (2002). Expression of vascular endothelial growth factor in canine mammary tumors. Veterinary Pathology, 39 (4), 488-493.
• 137. Rivera, P., Melin, M., Biagi, T., Fall, T., Haggström, J., Lindblad-Toh, K., von Euler, H. (2009). Mammary tumor development in dogs is associated with BRCA1 and BRCA2. Cancer Research, 69 (22), 8770-8774.
• 138. Rodrigues, H., Carvalho, M. I., Pires, I., Prada, J., & Queiroga, F. L. (2016). Clinicopathological significance of caspase-3 and ki-67 expression in canine mammary gland tumours. Acta Veterinaria Hungarica, 64 (1), 78-89.
• 139. Rudland, P. S., Platt-Higgins, A., Renshaw, C., West, C. R., Winstanley, J. H., Robertson, L., & Barraclough, R. (2000). Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. Cancer Research, 60 (6), 1595-1603.
• 140. Sagan, D., Kocki, T., Patel, S., & Kocki, J. (2015). Utility of kynurenic acid for non-invasive detection of metastatic spread to lymph nodes in non-small cell lung cancer. International Journal of Medicine, 12 (2), 146-153.
• 141. Sahabi, K., Selvarajah, G. T., Abdullah, R., Cheah, Y. K., & Tan, G. C. (2018). Comparative aspects of microRNA expression in canine and human cancers. Journal of Veterinary Science, 19 (2), 162-171.
• 142. Salama, I., Malone, P. S., Mihaimeed, F., & Jones, J. L. (2008). A review of the S100 proteins in cancer. European Journal of Surgical Oncology, 34 (4), 357-364.
• 143. Scheuner, D., Song, B., McEwen, E., Liu, C., Laybutt, R., Gillespie, P., … & Kaufman, R. J. (2001). Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Molecular Cell, 7 (6), 1165-1176.
• 144. Santos, A. A., Lopes, C. C., Ribeiro, J. R., Martins, L. R., Santos, J. C., Amorim, I. F., … & Matos, A. J. (2013). Identification of prognostic factors in canine mammary malignant tumours: a multivariable survival study. BMC Veterinary Research, 9 (1), 1.
• 145. Scholzen, T., & Gerdes, J. (2000). The Ki‐67 protein: from the known and the unknown. Journal of Cellular Physiology, 182 (3), 311-322.
• 146. Shi, Q. M., Luo, J., Wu, K., Yin, M., Gu, Y. R., & Cheng, X. G. (2016). High level of αB-crystallin contributes to the progression of osteosarcoma. Oncotarget, 7 (8), 9007.
• 147. Shweiki, D., Itin, A., Soffer, D., & Keshet, E. (1992). Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature, 359 (6398), 843-845.
• 148. Sivadasan, P., Gupta, M. K., Sathe, G. J., Balakrishnan, L., Palit, P., Gowda, H., … & Sirdeshmukh, R. (2015). Human salivary proteome—a resource of potential biomarkers for oral cancer. Journal of Proteomics, 127, 89-95.
• 149. Sleeckx, N., De Rooster, H., Veldhuis Kroeze, E. J. B., Van Ginneken, C., & Van Brantegem, L. (2011). Canine mammary tumours, an overview. Reproduction in Domestic Animals, 46 (6), 1112-1131.
• 150. Sorenmo, K. (2003). Canine mammary gland tumors. Veterinary Clinics of North America Small Animal Practice, 33 (3), 573-596.
• 151. Souza, J. V. (2002). Marker mucinous cancer associated. Revista Assoc Med Rio Grande Do Soul, 46, 70.
• 152. Szczubiał, M., Krawczyk, M., Bochniarz, M., Dąbrowski, R., Łopuszyński, W., & Urban-Chmiel, R. (2018). Comparison of plasma interleukin-6 and interleukin-10 concentrations between female dogs with mammary gland tumours and healthy. Pakistan Veterinary Journal, 38 (2), 194-198.
• 153. Takahashi, Y., Kitadai, Y., Bucana, C. D., Cleary, K. R., & Ellis, L. M. (1995). Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Research, 55 (18), 3964-3968.
• 154. Takeichi, M. (1990). Cadherins: a molecular family important in selective cell-cell adhesion. Annual Review of Biochemistry, 59 (1), 237-252.
• 155. Tavares, W. L., Lavalle, G. E., Figueiredo, M. S., Souza, A. G., Bertagnolli, A. C., Viana, F. A. B., … & Cassali, G. D. (2010). Evaluation of adverse effects in tamoxifen exposed healthy female dogs. Acta Veterinaria Scandinavica, 52 (1), 67.
• 156. Tavasoly, A., Golshahi, H., Rezaie, A., & Farhadi, M. (2013). Classification and grading of canine malignant mammary tumors. Veterinary Research Forum, 4 (1), 25-30.
• 157. Vakkala, M., Pääkkö, P., & Soini, Y. (1999). Expression of caspases 3, 6 and 8 is increased in parallel with apoptosis and histological aggressiveness of the breast lesion. British Journal of Cancer, 81 (4), 592-599.
• 158. Valko-Rokytovská, M., Očenáš, P., Salayová, A., & Kostecká, Z. (2018). New developed UHPLC method for selected urine metabolites. Journal of Chromatography and Separation Techniques, 9 (404), 2.
• 159. Valko-Rokytovská M, Očenáš P, Salayová A, Titková R, Kostecká Z (2020). Specific urinary metabolites in canine mammary gland tumors. J Vet Sci, 21 (2), e23.
• 160. Varallo, G. R., Gelaleti, G. B., Maschio Signorini, L. B., Moschetta, M. G., Lopes, J. r., De Nardi, A. B., … & De Campos Zuccari, D. A. (2019). Prognostic phenotypic classification for canine mammary tumors. Oncology Letters, 18 (6), 6545-6553.
• 161. Veldhoen, N., Watterson, J., Brash, M., & Milner, J. (1999). Identification of tumour-associated and germ line p53 mutations in canine mammary cancer. British Journal of Cancer, 81 (3), 409-415.
• 162. Von Kleist, S., Migule, I., & Halla, B. (1995). Possible function of CEA as cell-contact inhibitory molecule. Anticancer Research, 15 (5B), 1889.
• 163. Wiggins, T., Kumar, S., Markar, S. R., Antonowicz, S., & Hanna, G. B. (2015). Tyrosine, phenylalanine, and tryptophan in gastroesophageal malignancy: a systematic review. Cancer Epidemiology, Biomarkers & Prevention, 24 (1), 32-38.
• 164. Yarden, Y., & Sliwkowski, M. X. (2001). Untangling the ErbB signalling network. Nature Reviews Molecular Cell Biology, 2 (2), 127-137. 165. Yildirim, F., Sonmez, K., Ozyogurtcu, H., Sennazlı, G., Gurel, A., Gunduz, M. C., & Sontas, B. H. (2013). Evaluation of Bcl-2, Bcl-XL and Bax Expression and Apoptotic Index in Canine Mammary Tumors. Kafkas Üniversitesi Veteriner Fakultesi Dergisi, 20 (4), 513-520.
• 166. Yoshikawa, Y., Morimatsu, M., Ochiai, K., Ishigura-Oonuma, T., Wada, S., Orino, K., & Watanabe, K. (2015). Reduced canine BRCA2 expression levels in mammary gland tumors. BMC Veterinary Research, 11 (1), 159.
• 167. Zajkowska, M., Głażewska, E. K., Będkowska, G. E., Chorąży, P., Szmitkowski, M., & Ławicki, S. (2016). Diagnostic power of vascular endothelial growth factor and macrophage colony-stimulating factor in breast cancer patients based on ROC analysis. Mediators of Inflammation. 2016.
• 168. Zapata, J. M., Krajewska, M., Krajewski, S., Huang, R. P., Takayama, S., Wang, H. G., … & Reed, J. C. (1998). Expression of multiple apoptosis-regulatory genes in human breast cancer cell lines and primary tumors. Breast Cancer Research Treatment, 47 (2), 129-140.
• 169. Zeng, J. C., Zhang, Z., Li, T. Y., Liang, Y. F., Wang, H. M., Bao, J. J., … & Xu, J. F. (2013). Assessing the role of IL-35 in colorectal cancer progression and prognosis. International Journal of Clinical and Experimental Pathology, 6 (9), 1806.
• 170. Zha, C., Jiang, X. H., & Peng, S. F. (2015). iTRAQ-based quantitative proteomic analysis on S100 calcium binding protein A2 in metastasis of laryngeal cancer. Public Library of Science One, 10 (4), e0122322.
• 171. Zhang, S., Wang, Z., Liu, W., Lei, R., Shan, J., Li, L., & Wang, X. (2017). Distinct prognostic values of S100 mRNA expression in breast cancer. Scientific Reports, 7 (1), 1-11.
• 172. Zhang, Y., Sun, H., Wu, H., Tan, Q., & Xiang, K. (2015). Interleukin 35 is an independent prognostic factor and a therapeutic target for nasopharyngeal carcinoma. Contemporary Oncology, 19 (2), 120.
• 173. Zingg, H. H., & Laporte, S. A. (2003). The oxytocin receptor. Trends Endocrinology Metabolism, 14 (5), 222-227.
• 174. Zuccari, D. A., Santana, A. E., Cury, P. M., & Cordeiro, J. A. (2004). Immunocytochemical study of Ki‐67 as a prognostic marker in canine mammary neoplasia. Veterinary Clinical Pathology, 33 (1), 23-28.