The Protein Biomarkers of Feline Mammary Carcinoma https://doi.org/10.12982/VIS.2025.020

Main Article Content

Wajahat Masood
Abdul Wahab Ali
Afnaz Shaheen
Aeman Zulfiqar
Muhammad Saad Ul Haq
Syed Ali Raza
Ahsan Ashraf
Mehrullah

Abstract

Feline mammary carcinoma (FMC) is a prevalent aggressive malignancy in cats, characterized by a poor prognosis and limited treatment options beyond mastectomy. This review explores the significance of various protein biomarkers, including HER2, BCL-2, RON, Ki 67, and COX-2, in diagnosing and treating FMC in cats. Early diagnosis and treatment due to the aggressive nature of FMC is important, which often leads to limited therapeutic options and poor responses in later stages. Biomarkers play a crucial role in improving diagnostic accuracy, guiding therapeutic decisions, and monitoring disease progression in cats with FMC. The review highlights the potential of biomarkers to revolutionize diagnostic approaches in veterinary clinics, offering a more targeted and effective strategy for managing feline mammary carcinomas.

Article Details

How to Cite
Masood, W., Abdul Wahab Ali, Afnaz Shaheen, Aeman Zulfiqar, Muhammad Saad Ul Haq, Syed Ali Raza, Ahsan Ashraf, & Mehrullah. (2024). The Protein Biomarkers of Feline Mammary Carcinoma: https://doi.org/10.12982/VIS.2025.020. Veterinary Integrative Sciences, 23(1), 1–25. Retrieved from https://he02.tci-thaijo.org/index.php/vis/article/view/268200
Section
Review Article

References

Abdelrahman, A.E., Rashed, H.E., Abdelgawad, M., Abdelhamid, M.I., 2017. Prognostic impact of EGFR and cytokeratin 5/6 immunohistochemical expression in triple-negative breast cancer. Ann. Diagn. Pathol. 28, 43-53.

Al-Alem, U., Rauscher, G.H., Alem, Q.A., Kajdacsy-Balla, A., Mahmoud, A.M., 2023. Prognostic value of SGK1 and Bcl-2 in invasive breast cancer. Cancers. 15(12), 3151.

Ameer, T., 2023. Overview of feline mammary tumors. Biological Times. 2, 15-16.

Andò, S., Gelsomino, L., Panza, S., Giordano, C., Bonofiglio, D., Barone, I., Catalano, S., 2019. Obesity, leptin, and breast cancer: epidemiological evidence and proposed mechanisms. Cancers. 11(1), 62.

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. Res. Vet. Sci. 106, 121-130.

Ariyarathna, H., Thomson, N.A., Aberdein, D., Perrott, M.R., Munday, J.S., 2020. Increased programmed death ligand (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) expression are associated with metastasis and poor prognosis in malignant canine mammary gland tumors. Vet. Immunol. Immunopathol. 230, 110142.

Bally, A.P., Austin, J.W., Boss, J.M., 2016. Genetic and epigenetic regulation of PD-1 expression. J. Immunol. 196, 2431-2437.

Baumeister, S.H., Freeman, G.J., Dranoff, G., Sharpe, A.H., 2016. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol. 34, 539-573.

Behera, R., Kumar, V., Lohite, K., Karnik, S., Kundu, G.C., 2010. Activation of JAK2/STAT3 signaling by osteopontin promotes tumor growth in human breast cancer cells. Carcinogenesis. 31(2), 192-200.

Bertagnolli, A.C., Ferreira, E., Dias, E.J., Cassali, G.D., 2011. Canine mammary mixed tumors: immunohistochemical expressions of EGFR and HER‐2. Aust. Vet. J. 89(8), 312-317.

Blackford, A.N., Nieminuszczy, J., Schwab, R.A., Galanty, Y., Jackson, S.P., Niedzwiedz, W., 2015. TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation. Molecular. Cell. 57(6), 1133–1141.

Boise, L.H., González-García, M., Postema, C.E., Ding, L., Lindsten, T., Turka, L.A., Thompson, C.B., 1993. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 74(4), 597-608.

Bramwell, V.H., Doig, G.S., Tuck, A.B., Wilson, S.M., Tonkin, K.S., Tomiak, A., Chambers, A.F., 2006. Serial plasma osteopontin levels have prognostic value in metastatic breast cancer. Clin. Cancer. Res. 12(11), 3337-3343.

Brunetti, B., Asproni, P., Beha, G., Muscatello, L.V., Millanta, F., Poli, A., Sarli, G., 2013. The molecular phenotype in mammary tumours of queens: correlation between primary tumour and lymph node metastasis. J. Comp. Pathol. 148(2-3), 206-213.

Burugu, S., Gao, D., Leung, S., Chia, S.K., Nielsen, T.O., 2017. LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors. Ann. Oncol. 28(12), 2977-2984.

Campos, L.C., Silva, J.O., Santos, F.S., Araújo, M.R., Lavalle, G.E., Ferreira, E., Cassali, G.D., 2015. Prognostic significance of tissue and serum HER2 and MUC1 in canine mammary cancer. J. Vet. Diagn. Invest. 27(4), 531-535.

Cao, X., Ren, X., Zhou, Y., Mao, F., Lin, Y., Wu, H., Sun, Q., 2021. VISTA expression on immune cells correlates with favorable prognosis in patients with triple-negative breast cancer. Front. Oncol. 10, 583966.

Cescutti, R., Negrini, S., Kohzaki, M., Halazonetis, T.D., 2010. TopBP1 functions with 53BP1 in the G1 DNA damage checkpoint. Embo. J. 29(21), 3723–3732.

Chandrasekharan, N.V., Simmons, D.L., 2004. The cyclooxygenases. Genome. Biol. 5, 1-7.

Chen, L., 2004. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 4(5), 336-347.

Chen, Y., Cui, T., Yang, L., Mireskandari, M., Knoesel, T., Zhang, Q., Petersen, I., 2011. The diagnostic value of cytokeratin 5/6, 14, 17, and 18 expression in human non-small cell lung cancer. Oncology. 80(5-6), 333-340.

Chocteau, F., Boulay, M.M., Besnard, F., Valeau, G., Loussouarn, D., Nguyen, F., 2019. Proposal for a histological staging system of mammary carcinomas in dogs and cats. Part 2: feline mammary carcinomas. Front. Vet. Sci. 6, 387.

Clemente, M., Sánchez-Archidona, A.R., Sardón, D., Díez, L., Martín-Ruiz, A., Caceres, S., Peña, L., 2013. Different role of COX-2 and angiogenesis in canine inflammatory and non-inflammatory mammary cancer. Vet. J. 197(2), 427-432.

Coombes, J.D., Choi, S.S., Swiderska-Syn, M., Manka, P., Reid, D.T., Palma, E., Syn, W.K., 2016. Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis. BBA Mol. Basis Dis. 1862(1), 135-144.

Dąbrowska, E., Przylipiak, A., Zajkowska, M., Piskor, B.M., Sidorkiewicz, I., Szmitkowski, M., Lawicki, S., 2020. Possible diagnostic application of CXCL12 and CXCR4 as tumor markers in breast cancer patients. Anticancer. Res. 40(6), 3221-3229.

Dagher, E., Abadie, J., Loussouarn, D., Fanuel, D., Campone, M., Nguyen, F., 2019. Bcl-2 expression and prognostic significance in feline invasive mammary carcinomas: a retrospective observational study. BMC. Vet. Res. 15, 1-13.

Danilkovitch-Miagkova, A., 2003. Oncogenic signaling pathways activated by RON receptor tyrosine kinase. Curr. Cancer. Drug. Targets. 3(1), 31-40.

Delacroix, S., Wagner, J.M., Kobayashi, M., Yamamoto, K., Karnitz, L.M., 2007. The Rad9-Hus1-Rad1 (9–1-1) clamp activates checkpoint signaling via TopBP1. Genes. Dev. 21(12), 1472–1477.

Dewan, M.Z., Ahmed, S., Iwasaki, Y., Ohba, K., Toi, M., Yamamoto, N., 2006. Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed. Pharmacother. 60(6), 273-276.

Dey, P., Togra, J., Mitra, S., 2014. Intermediate filament: structure, function, and applications in cytology. Diagn. Cytopathol. 42(7), 628-635.

Ding, Y., Chen, J., Cui, G., Wei, Y., Lu, C., Wang, L., Diao, H., 2016. Pathophysiological role of osteopontin and angiotensin II in atherosclerosis. Biochem. Biophys. Res. Commun. 471(1), 5-9.

Dong, P., Xiong, Y., Yue, J., Hanley, S.J., Watari, H., 2018. Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment: beyond immune evasion. Front. Oncol. 8, 386.

Dubois, R.N., Abramson, S.B., Crofford, L., Gupta, R.A., Simon, L.S., Van De Putte, L.B., Lipsky, P.E., 1998. Cyclooxygenase in biology and disease. FASEB J. 12(12), 1063-1073.

Dunstan, R.W., Wharton Jr, K.A., Quigley, C., Lowe, A., 2011. The use of immunohistochemistry for biomarker assessment—can it compete with other technologies? Toxicol. Pathol. 39(6), 988-1002.

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. Braz. J. Med. Biol. Res. 37, 1673-1681.

Elston, C.W., Ellis, I.O., 1991. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long‐term follow‐up. Histopathology. 19(5), 403-410.

ElTanbouly, M.A., Schaafsma, E., Smits, N.C., Shah, P., Blazar, B.R., Noelle, R.J., Mabaera, R., 2020. VISTA re-programs macrophage biology through the combined regulation of tolerance and anti-inflammatory pathways. Front. Immunol. 11, 580187.

Eyob, H., Ekiz, H.A., Welm, A.L., 2013. RON promotes the metastatic spread of breast carcinomas by subverting antitumor immune responses. Oncoimmunology. 2(9), 25670.

Frenzel, A., Grespi, F., Chmelewskij, W., Villunger, A., 2009. Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis. 14, 584-596.

Füzéry, A.K., Levin, J., Chan, M.M., Chan, D.W., 2013. Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges. Clin. Proteomics. 10, 1-14.

Gameiro, A., Nascimento, C., Correia, J., Ferreira, F., 2021. VISTA Is a diagnostic biomarker and immunotherapy target of aggressive feline mammary carcinoma subtypes. Cancers. 13(21), 5559.

Gameiro, A., Urbano, A.C., Ferreira, F., 2021. Emerging biomarkers and targeted therapies in feline mammary carcinoma. Vet. Sci. 8(8), 164.

Gameiro, A., Nascimento, C., Urbano, A.C., Correia, J., Ferreira, F., 2021. Serum and tissue expression levels of lepti

n and leptin receptor are putative markers of specific feline mammary carcinoma subtypes. Front. Vet. Sci. 8, 625147.

Gao, J., Ward, J.F., Pettaway, C.A., Shi, L.Z., Subudhi, S.K., Vence, L.M., Sharma, P., 2017. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat. Med. 23(5), 551-555.

Garofalo, C., Koda, M., Cascio, S., Sulkowska, M., Kanczuga-Koda, L., Golaszewska, J., Surmacz, E., 2006. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin. Cancer Res. 12(5), 1447-1453.

Gelmini, S., Mangoni, M., Serio, M., Romagnani, P., Lazzeri, E., 2008. The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis. J. Endocrinol. Investig. 31, 809-819.

Giménez, F., Hecht, S., Craig, L.E., Legendre, A.M., 2010. Early detection, aggressive therapy: optimizing the management of feline mammary masses. J. Feline Med. Surg. 12(3), 214-224.

Going, J.J., Nixon, C., Dornan, E.S., Boner, W., Donaldson, M.M., Morgan, I.M., 2007. Aberrant expression of TopBP1 in breast cancer. Histopathology. 50(4), 418-424.

Goldhirsch, A., Winer, E.P., Coates, A.S., Gelber, R.D., Piccart-Gebhart, M., Thürlimann, B., Wood, W.C., 2013. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann. Oncol. 24(9), 2206-2223.

Gong, Z., Kim, J.E., Leung, C.C., Glover, J.N., Chen, J., 2010. BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Molecular Cell. 37(3), 438–446.

Görlinger, S., Kooistra, H.S., Van den Broek, A., Okkens, A.C., 2002. Treatment of fibroadenomatous hyperplasia in cats with aglepristone. J. Vet. Intern. Med. 16(6), 710-713.

Greenhough, A., Smartt, H.J., Moore, A.E., Roberts, H.R., Williams, A.C., Paraskeva, C., Kaidi, A., 2009. The COX-2/PGE 2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 30(3), 377-386.

Gregório, H., Raposo, T., Queiroga, F.L., Pires, I., Pena, L., Prada, J., 2017. High COX‐2 expression in canine mast cell tumours is associated with proliferation, angiogenesis and decreased overall survival. Vet. Comp. Oncol. 15(4), 1382-1392.

Grisoni Sanchez, C., Figueiredo, M.L., de Sartori Camargo, L., Benevenuto, L.G.D., Lacerda, Z.A., Fonseca-Alves, C.E., 2023. Is Osteopontin a good marker for bone metastasis in canine mammary gland tumor and prostate cancer?. Animals. 13(20), 3211.

Guo, S., Liu, M., Wang, G., Torroella-Kouri, M., Gonzalez-Perez, R.R., 2012. Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells. Biochim. Biophys. Acta (BBA) - Rev. Cancer. 1825(2), 207-222.

Gurel, A., Sonta, M.C.G.B.H., 2014. Evaluation of Bd-2, Bd-XL and Bax expression and apoptotic index in canine mammary tumours [1]. Kafkas. Univ. Vet. Fak. Derg. 20(4), 513-520.

Hahn, K.A., Bravo, L., Avenell, J.S., 1994. Feline breast carcinoma as a pathologic and therapeutic. In. Vivo. 8, 825-828.

Hashmi, A.A., Hussain, Z.F., Irfan, M., Edhi, M.M., Kanwal, S., Faridi, N., Khan, A., 2018. Cytokeratin 5/6 expression in bladder cancer: association with clinicopathologic parameters and prognosis. BMC. Res. Notes. 11, 1-5.

Havel, P.J., 2000. Role of adipose tissue in body-weight regulation: mechanisms regulating leptin production and energy balance. Proc. Nutr. Soc. 59(3), 359-371.

Hayes Jr, H.M., Milne, K.L., Mandell, C.P., 1981. Epidemiological features of feline mammary carcinoma. Vet. Rec. 108(22), 476-479.

Hu, P., Liu, Q., Deng, G., Zhang, J., Liang, N., Xie, J., Zhang, J., 2017. The prognostic value of cytotoxic T-lymphocyte antigen 4 in cancers: a systematic review and meta-analysis. Sci. Rep.7(1), 42913.

Hunt, B.G., Fox, L.H., Davis, J.C., Jones, A., Lu, Z., Waltz, S.E., 2023. An introduction and overview of RON receptor tyrosine kinase signaling. Genes. 14(2), 517.

Hunt, B.G., Wicker, C.A., Bourn, J.R., Lower, E.E., Takiar, V., Waltz, S.E., 2020. MST1R (RON) expression is a novel prognostic biomarker for metastatic progression in breast cancer patients. Breast. Cancer. Res. Treat. 181, 529-540.

Hwang, K.T., Kim, Y.A., Kim, J., Oh, H.J., Park, J.H., Choi, I.S., Hwang, K.R., 2021. Prognostic influences of BCL1 and BCL2 expression on disease-free survival in breast cancer. Sci. Rep. 11(1), 11942.

Igase, M., Inanaga, S., Tani, K., Nakaichi, M., Sakai, Y., Sakurai, M., Mizuno, T., 2022. Long‐term survival of dogs with stage 4 oral malignant melanoma treated with anti‐canine PD‐1 therapeutic antibody: A follow‐up case report. Vet. Comp. Oncol. 20(4), 901-905.

Ivković, K.T., Panjković, M., Nikolić, I., Đilas, I.D., Knežević, U.S., 2012. Expression of cytokeratins 5/6 and cytokeratin 17 in invasive breast carcinoma. Vojnosanit. Pregl. 69(12), 1031-1038.

Jardé, T., Caldefie-Chézet, F., Damez, M., Mishellany, F., Penault-Llorca, F., Guillot, J., Vasson, M.P., 2008. Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol. Rep. 19(4), 905-911.

Johnston, R.J., Su, L.J., Pinckney, J., Critton, D., Boyer, E., Krishnakumar, A., Korman, A.J., 2019. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 574(7779), 565-570.

Juin, P., Geneste, O., Gautier, F., Depil, S., Campone, M., 2013. Decoding and unlocking the BCL-2 dependency of cancer cells. Nat. Rev. Cancer. 13(7), 455-465.

Kabir, N.N., Rönnstrand, L., Kazi, J.U., 2014. Keratin 19 expression correlates with poor prognosis in breast cancer. Mol. Biol. Rep. 41, 7729-7735.

Kariya, Y., Kariya, Y., 2022. Osteopontin in cancer: mechanisms and therapeutic targets. Int. J. Transl. Med. 2(3), 419-447.

Khleif, S.N., Doroshow, J.H., Hait, W.N., 2010. AACR-FDA-NCI Cancer Biomarkers Collaborative consensus report: advancing the use of biomarkers in cancer drug development. Clin. Cancer. Res. 16(13), 3299-3318.

Kim, H.M., Lee, J., Koo, J.S., 2017. Clinicopathological and prognostic significance of programmed death ligand-1 expression in breast cancer: a meta-analysis. BMC Cancer. 17, 1-11.

Leimbacher, P.A., Jones, S.E., Shorrocks, A.K., de Marco Zompit, M., Day, M., Blaauwendraad, J., Bundschuh, D., Bonham, S., Fischer, R., Fink, D., Kessler, B.M., Oliver, A.W., Pearl, L.H., Blackford, A.N., Stucki, M., 2019. MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis. Mol. Cell. 74(3), 571-583.

Liang, Z., Yoon, Y., Votaw, J., Goodman, M.M., Williams, L., Shim, H., 2005. Silencing of CXCR4 blocks breast cancer metastasis. Cancer. Res. 65(3), 967-971.

Linjawi, A., Kontogiannea, M., Halwani, F., Edwardes, M., Meterissian, S., 2004. Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer. J. Am. Coll. Surg. 198(1), 83-90.

Liu, K., Bellam, N., Lin, H.Y., Wang, B., Stockard, C.R., Grizzle, W.E., Lin, W.C., 2009. Regulation of p53 by TopBP1: A potential mechanism for p53 inactivation in cancer. Mol. Cell. Biol. 29(10), 2673–2693.

Liu, Q., Hu, P., Deng, G., Zhang, J., Liang, N., Xie, J., Zhang, J., 2017. Soluble cytotoxic T-lymphocyte antigen 4: a favorable predictor in malignant tumors after therapy. OncoTargets Ther. 2147-2154.

Ma, Y., Fan, M., Dai, L., Kang, X., Liu, Y., Sun, Y., Chen, K., 2015. Expression of p63 and CK5/6 in early‐stage lung squamous cell carcinoma is not only an early diagnostic indicator but also correlates with a good prognosis. Thorac. Cancer. 6(3), 288-295.

Madewell, B.R., Candour-Edwards, R., Edwards, B.F., Walls, J.E., Griffey, S.M., 1999. Topographic distribution of bcl-2 protein in feline tissues in health and neoplasia. Vet. Pathol. 36(6), 565-573.

Maeda, T., Nakanishi, Y., Hirotani, Y., Fuchinoue, F., Enomoto, K., Sakurai, K., Nemoto, N., 2016. Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer. Med. Mol. Morphol. 49, 11-21.

Mai, K.T., Ball, C.G., Belanger, E.C., 2016. Noninvasive papillary basal-like urothelial carcinoma: a subgroup of urothelial carcinomas with immunohistochemical features of basal urothelial cells associated with a high rate of recurrence and progression. Appl. Immunohistochem. Mol. Morphol. 24(8), 575-582.

Magi, G.E., Mariotti, F., Pallotta, L., Di Cerbo, A., Venanzi, F.M., 2022. Immunohistochemical expression of p62 in feline mammary carcinoma and non-neoplastic mammary tissue. Animals. 12(15), 1964.

Makawita, S., Diamandis, E.P., 2010. The bottleneck in the cancer biomarker pipeline and protein quantification through mass spectrometry–based approaches: current strategies for candidate verification. Clin. Chem. 56(2), 212-222.

Maniscalco, L., Guil-Luna, S., Iussich, S., Gattino, F., Trupia, C., Millan, Y., De Maria, R., 2019. Expression of the short form of RON/STK in feline mammary carcinoma. Vet. Pathol. 56(2), 220-229.

Margetic, S., Gazzola, C., Pegg, G.G., Hill, R.A., 2002. Leptin: a review of its peripheral actions and interactions. Int. J. Obes. Relat. Metab. Disord. 26(11), 1407-1433.

Marques, C., Correia, J., Ferreira, F., 2016. HER2-positive feline mammary carcinoma. Aging (Albany NY). 8(8), 1574.

Marques, C.S., Santos, A.R., Gameiro, A., Correia, J., Ferreira, F., 2018. CXCR4 and its ligand CXCL12 display opposite expression profiles in feline mammary metastatic disease, with the exception of HER2-overexpressing tumors. BMC. Cancer. 18, 1-13.

Marques, C.S., Soares, M., Santos, A., Correia, J., Ferreira, F., 2017. Serum SDF-1 levels are a reliable diagnostic marker of feline mammary carcinoma, discriminating HER2-overexpressing tumors from other subtypes. Oncotarget. 8(62), 105775.

Masood, S., Bui, M.M., 2002. Prognostic and predictive value of HER2/neu oncogene in breast cancer. Microsc. Res. Tech. 59(2), 102-108.

Masood, W., 2024. The general and systemic consequences of obesity in cats and dogs. Vet. Integr. Sci. 20(1), 265-290

McDermott, D.F., Atkins, M.B., 2013. PD‐1 as a potential target in cancer therapy. Cancer. Med. 2(5), 662-673.

McDonald, K.A., Kawaguchi, T., Qi, Q., Peng, X., Asaoka, M., Young, J., Takabe, K., 2019. Tumor heterogeneity correlates with less immune response and worse survival in breast cancer patients. Ann. Surg. Oncol. 26, 2191-2199.

Ménard, S., Fortis, S., Castiglioni, F., Agresti, R., Balsari, A., 2001. HER2 as a prognostic factor in breast cancer. Oncology. 61(2), 67-72.

Maniscalco, L., Guil-Luna, S., Iussich, S., Gattino, F., Trupia, C., Millan, Y., De Maria, R., 2019. Expression of the short form of RON/STK in feline mammary carcinoma. Vet. Pathol. 56(2), 220-229.

Michishita, M., Ohtsuka, A., Nakahira, R., Tajima, T., Nakagawa, T., Sasaki, N., Takahashi, K., 2016. Anti-tumor effect of bevacizumab on a xenograft model of feline mammary carcinoma. J. Vet. Med. Sci. 78(4), 685-689.

Millanta, F., Asproni, P., Canale, A., Citi, S., Poli, A., 2016. COX‐2, mPGES‐1 and EP2 receptor immunohistochemical expression in canine and feline malignant mammary tumours. Vet. Comp. Oncol. 14(3), 270-280.

Millanta, F., Calandrella, M., Bari, G., Niccolini, M., Vannozzi, I., Poli, A., 2005a. Comparison of steroid receptor expression in normal, dysplastic, and neoplastic canine and feline mammary tissues. Res. Vet. Sci. 79(3), 225-232.

Millanta, F., Calandrella, M., Citi, S., Della Santa, D., Poli, A., 2005b. Overexpression of HER-2 in feline invasive mammary carcinomas: an immunohistochemical survey and evaluation of its prognostic potential. Vet. Pathol. 42(1), 30-34.

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. Res. Treat. 98, 115-120.

Millar, R., Kilbey, A., Remak, S.J., Severson, T.M., Dhayade, S., Sandilands, E., Coffelt, S.B., 2020. The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer. Mol. Oncol. 14(8), 1868-1880.

Mills, S.W., Musil, K.M., Davies, J.L., Hendrick, S., Duncan, C., Jackson, M.L., Simko, E., 2015. Prognostic value of histologic grading for feline mammary carcinoma:a retrospective survival analysis. Vet. Pathol. 52(2), 238-249.

Misdorp, W., Romijn, A., Hart, A.A., 1991. Feline mammary tumors: a case-control study of hormonal factors. Anticancer. Res. 11(5), 1793-1797.

Moll, R., Divo, M., Langbein, L., 2008. The human keratins: biology and pathology. Histochem. Cell. Biol. 129, 705-733.

Moorman, H.R., Poschel, D., Klement, J.D., Lu, C., Redd, P.S., Liu, K., 2020. Osteopontin: a key regulator of tumor progression and immunomodulation. Cancers. 12(11), 3379.

Morris, J., 2013. Mammary tumours in the cat: size matters, so early intervention saves lives. J. Feline. Med. Surg. 15(5), 391-400.

Morris, J.S., Nixon, C., Bruck, A., Nasir, L., Morgan, I.M., Philbey, A.W., 2008. Immunohistochemical expression of TopBP1 in feline mammary neoplasia in relation to histological grade, Ki67, ERα and p53. Vet. J. 175(2), 218-226.

Morris, J.S., Nixon, C., King, O.J., Morgan, I.M., Philbey, A.W., 2009. Expression of TopBP1 in canine mammary neoplasia in relation to histological type, Ki67, ERα and p53. Vet. J. 179(3), 422-429.

Moudry, P., Watanabe, K., Wolanin, K.M., Bartkova, J., Wassing, I.E., Watanabe, S., Strauss, R., Troelsgaard Pedersen, R., Oestergaard, V.H., Lisby, M., Andújar-Sánchez, M., Maya-Mendoza, A., Esashi, F., Lukas, J., Bartek, J., 2016. TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. J. Cell. Biol. 212(3), 281-288.

Murray, J.K., Gruffydd‐Jones, T.J., Roberts, M.A., Browne, W.J., 2015. Assessing changes in the UK pet cat and dog populati

ons: numbers and household ownership. Vet. Rec. 177(10), 259-259.

Muscatello, L.V., Di Oto, E., Sarli, G., Monti, V., Foschini, M.P., Benazzi, C., Brunetti, B., 2019. HER2 amplification status in feline mammary carcinoma: a tissue microarray–fluorescence in situ hydridization–based study. Vet. Pathol. 56(2), 230-238.

Nascimento, C., Urbano, A.C., Gameiro, A., Ferreira, J., Correia, J., Ferreira, F., 2020. Serum PD-1/PD-L1 levels, tumor expression and PD-L1 somatic mutations in HER2-positive and triple negative normal-like feline mammary carcinoma subtypes. Cancers. 12(6), 1386.

Naserabad, S.A.R., Bagheri, S., Kheradmand, P., Latifi, S.M., 2023. Investigating the expression of cytokeratin 5/6 in benign and malignant breast lesions. Immunopathol. Persa. x(x), 39477.

Nascimento, C., Urbano, A.C., Gameiro, A., Ferreira, J., Correia, J., Ferreira, F., 2020. Serum PD-1/PD-L1 levels, tumor expression and PD-L1 somatic mutations in HER2-positive and triple negative normal-like feline mammary carcinoma subtypes. Cancers. 12(6), 1386.

Noske, A., Möbus, V., Weber, K., Schmatloch, S., Weichert, W., Köhne, C.H., Denkert, C., 2019. Relevance of tumour-infiltrating lymphocytes, PD-1 and PD-L1 in patients with high-risk, nodal-metastasised breast cancer of the German Adjuvant Intergroup Node–positive study. Eur. J. Cancer. 114, 76-88.

Novosad, C.A., Bergman, P.J., O’Brien, M.G., McKnight, J.A., Charney, S.C., Selting, K.A., Gieger, T.L., 2006. Retrospective evaluation of adjunctive doxorubicin for the treatment of feline mammary gland adenocarcinoma: 67 cases. J. Am. Anim. Hosp. Assoc. 42(2), 110-120.

Ohaegbulam, K.C., Assal, A., Lazar-Molnar, E., Yao, Y., Zang, X., 2015. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends. Mol. Med. 21(1), 24-33.

Oltval, Z.N., Milliman, C.L., Korsmeyer, S.J., 1993. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death. Cell. 74(4), 609-619.

Overley, B., Shofer, F.S., Goldschmidt, M.H., Sherer, D., Sorenmo, K.U., 2005. Association between ovarihysterectomy and feline mammary carcinoma. J. Vet. Intern. Med. 19(4), 560-563.

Owen, L.N., 1980. TNM Classification of Tumours in Domestic Animals/edited by LN Owen. WHO, Geneva

Ozmen, O., Haligur, M., Ipek, V., 2015. Immunohistochemical expression of osteopontin in canine and feline tumors. Rev. Med. Vet. 166, 2-10.

Papadaki, M.A., Koutsopoulos, A.V., Tsoulfas, P.G., Lagoudaki, E., Aggouraki, D., Monastirioti, A., Agelaki, S., 2020. Clinical relevance of immune checkpoints on circulating tumor cells in breast cancer. Cancers. 12(2), 376.

Pastuszak, M., Groszewski, K., Pastuszak, M., Dyrla, P., Wojtuń, S., Gil, J., 2015. Cytokeratins in gastroenterology. Systematic review. Gastroenterol. Rev. 10(2), 61-70.

Peñafiel-Verdu, C., Buendia, A.J., Navarro, J.A., Ramirez, G.A., Vilafranca, M., Altimira, J., Sanchez, J., 2012. Reduced expression of E-cadherin and β-catenin and high expression of basal cytokeratins in feline mammary carcinomas with regional metastasis. Vet. Pathol. 49(6), 979-987.

Pogorelyy, M.V., Fedorova, A.D., McLaren, J.E., Ladell, K., Bagaev, D.V., Eliseev, A. V., Shugay, M., 2018. Exploring the pre-immune landscape of antigen-specific T cells. Genome. Med. 10(1), 1-14.

Qin, T., Zeng, Y.D., Qin, G., Xu, F., Lu, J.B., Fang, W.F., Xue, C., Zhan, J.H., Zhang, X.K., Zheng, Q.F., Peng, R.J., Yuan, Z.Y., Zhang, L., Wang, S.S., 2015. High PD-L1 expression was associated with poor prognosis in 870 chinese patients with breast cancer. Oncotarget. 6(32), 33972-33981.

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. Res. Vet. Sci. 88(3), 441-445.

Rangaswami, H., Bulbule, A., Kundu, G.C., 2006. Osteopontin: role in cell signaling and cancer progression. Trends. Cell. Biol. 16(2), 79-87.

Rao, X., Wang, J., Song, H.M., Deng, B., Li, J.G., 2020. KRT15 overexpression predicts poor prognosis in colorectal cancer. Neoplasma. 67(2), 410-414.

Rasha, M.R., Yasmine, F.E., Ismail Amer, M.D., Samar, I., 2021. Immunohistochemical expression of leptin in mammary carcinoma. Med. J. Cairo Univ. 89(1), 285-296.

Raskin, R.E., 2016. General categories of cytologic interpretation. Canine Feline Cytology. 15-25.

Rezouki, I., Zohair, B., Ssi, S.A., Karkouri, M., Razzouki, I., Elkarroumi, M., Badou, A., 2023. High VISTA expression is linked to a potent epithelial-mesenchymal transition and is positively correlated with PD1 in breast cancer. Front. Oncol. 13, 1154631.

Rhea, J.M., Molinaro, R.J., 2011. Cancer biomarkers: surviving the journey from bench to bedside. MLO Med. Lab. Obs. 43(3), 10-12.

Rittling, S.R., Chambers, A.F., 2004. Role of osteopontin in tumour progression. Br. J. Cancer. 90(10), 1877-1881.

Rizzo, M.T., 2011. Cyclooxygenase-2 in oncogenesis. Clin. Chim. Acta. 412(9-10), 671-687.

Sabatier, R., Finetti, P., Mamessier, E., Adelaide, J., Chaffanet, M., Ali, H.R., Bertucci, F., 2015. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 6(7), 5449.

Safadi, R.A., Abdullah, N.I., Alaaraj, R.F., Bader, D.H., Divakar, D.D., Hamasha, A.A., Sughayer, M.A., 2019. Clinical and histopathologic prognostic implications of the expression of cytokeratins 8, 10, 13, 14, 16, 18 and 19 in oral and oropharyngeal squamous cell carcinoma. Arch. Oral. Biol. 99, 1-8.

Salmaninejad, A., Khoramshahi, V., Azani, A., Soltaninejad, E., Aslani, S., Zamani, M.R., Hosseini, S.M., 2018. PD-1 and cancer: molecular mechanisms and polymorphisms. Immunogenetics. 70, 73-86.

Sarker, D., Pacey, S., Workman, P., 2007. Use of pharmacokinetic/ pharmacodynamic biomarkers to support rational cancer drug development. Future. Med. 399-417.

Savli, T.B., Pasaoglu, H.E., Savli, T.C., Muhammedoglu, A., Tokocin, M., Öztürk, Ç., 2023. Expression of cytotoxic T lymphocyte-associated antigen 4, CD44, and E-cadherin in the microenvironment of breast carcinomas. Rev. Assoc. Med. Bras. 69, e20230371.

Senbanjo, L.T., Chellaiah, M.A., 2017. CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front. Cell. Dev. Biol. 5, 18.

Shimodaira, T., Matsuda, K., Uchibori, T., Sugano, M., Uehara, T., Honda, T., 2018. Upregulation of osteopontin expression via the interaction of macrophages and fibroblasts under IL-1b stimulation. Cytokine. 110, 63-69.

Simeonov, R., 2024. Correlation between fine-needle aspiration biopsy and routine histopathology in the diagnosis of spontaneous feline mammary gland tumours. Bulg. J. Vet. Med. 27(1), 16-33.

Soares, M., Correia, A.N., Batista, M.R., Correia, J., Ferreira, F., 2022. fHER2, PR, ER, Ki-67 and Cytokeratin 5/6 Expression in Benign Feline Mammary Lesions. Animals. 12(13), 1599.

Soares, M., Madeira, S., Correia, J., Peleteiro, M., Cardoso, F., Ferreira, F., 2016. Molecular based subtyping of feline mammary carcinomas and clinicopathological characterization. The Breast. 27, 44-51.

Soares, M., Ribeiro, R., Najmudin, S., Gameiro, A., Rodrigues, R., Cardoso, F., Ferreira, F., 2016. Serum HER2 levels are increased in cats with mammary carcinomas and predict tissue HER2 status. Oncotarget. 7(14), 17314.

Sokka, M., Parkkinen, S., Pospiech, H., Syväoja, J.E., 2010. Function of TopBP1 in genome stability. Genome Stability Hum. Dis. 50, 119-141.

Solinas, C., Carbognin, L., De Silva, P., Criscitiello, C., Lambertini, M., 2017. Tumor-infiltrating lymphocytes in breast cancer according to tumor subtype: current state of the art. The Breast. 35, 142-150.

Solinas, C., Garaud, S., De Silva, P., Boisson, A., Van den Eynden, G., de Wind, A., Willard-Gallo, K., 2017. Immune checkpoint molecules on tumor-infiltrating lymphocytes and their association with tertiary lymphoid structures in human breast cancer. Front. Immunol. 8, 1412.

Sorenmo, K.U., Worley, D.R., Goldschmidt, M.H., 2013. Tumors of the mammary gland. John Wiley & Sons, Hoboken, New Jersey, pp. 538-556.

Stovgaard, E.S., Nielsen, D., Hogdall, E., Balslev, E., 2018. Triple negative breast cancer - prognostic role of immune-related factors: a systematic review. Acta. Oncol. 57(1), 74-82.

Sun, X., Kaufman, P.D., 2018. Ki-67: more than a proliferation marker. Chromosoma. 127, 175-86.

Sysel, A.M., Valli, V.E., Bauer, J.A., 2015. Immunohistochemical quantification of the cobalamin transport protein, cell surface receptor and Ki-67 in naturally occurring canine and feline malignant tumors and in adjacent normal tissues. Oncotarget. 6(4), 2331.

Takayama, S., Sato, T., Krajewski, S., Kochel, K., Irie, S., Milian, J.A., Reed, J.C., 1995. Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell. 80(2), 279-284.

Tawfik, M.F., Oda, S.S., Khafaga, A.F., 2021. Pathological and immunohistochemical microscopy of natural cases of canine and feline neoplastic mammary lesions. Microsc. Microanal. 27(4), 910-922.

Teicher, B.A., Fricker, S.P., 2010. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin. Cancer Res. 16(11), 2927-2931.

Topalian, S.L., Drake, C.G., Pardoll, D.M., 2015. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer. Cell. 27(4), 450-461.

Tsé, C., Gauchez, A.S., Jacot, W., Lamy, P.J., 2012. HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer. Cancer Treat. Rev. 38(2), 133-142.

Tsujimoto, Y., Croce, C.M., 1986. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl. Acad. Sci. USA. 83(14), 5214-5218.

Urbano, A.C., Nascimento, C., Soares, M., Correia, J., Ferreira, F., 2020. Clinical Relevance of the serum CTLA-4 in cats with mammary carcinoma. Sci. Rep. 10(1), 3822.

Vail, D.M., Macewen, E.G., 2000. Spontaneously occurring tumors of companion animals as models for human cancer. Cancer. Invest. 18(8), 781-792.

Vasca, V., Vasca, E., Freiman, P., Marian, D., Luce, A., Mesolella, M., Duminica, T., 2014. Keratin 5 expression in squamocellular carcinoma of the head and neck. Oncol. Lett. 8(6), 2501-2504.

Völkel, C., De Wispelaere, N., Weidemann, S., Gorbokon, N., Lennartz, M., Luebke, A.M., Menz, A., 2022. Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications. Virchows Arch. 480(2), 433-447.

Vonderheide, R.H., Domchek, S.M., Clark, A.S., 2017. Immunotherapy for breast cancer: what are we missing?. Clin. Cancer. Res. 23(11), 2640-2646.

Wang, C., Zhu, H., Zhou, Y., Mao, F., Lin, Y., Pan, B., Sun, Q., 2017. Prognostic value of PD‐L1 in breast cancer: a meta‐analysis. Breast. J. 23(4), 436-443.

Wang, J., Wu, G., Manick, B., Hernandez, V., Renelt, M., Erickson, C., Kalabokis, V., 2019. VSIG‐3 as a ligand of VISTA inhibits human T‐cell function. Immunology. 156(1), 74-85.

Wang, L., Rubinstein, R., Lines, J.L., Wasiuk, A., Ahonen, C., Guo, Y., Noelle, R.J., 2011. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208(3), 577-592.

Wang, R.X., Ji, P., Gong, Y., Shao, Z.M., Chen, S., 2022. SDF-1 expression and tumor-infiltrating lymphocytes identify clinical subtypes of triple-negative breast cancer with different responses to neoadjuvant chemotherapy and survival. Front. Immunol. 13, 940635.

Wardlaw, C.P., Carr, A.M., Oliver, A.W., 2014. TopBP1: A BRCT-scaffold protein functioning in multiple cellular pathways. DNA repair. 22, 165-174.

Wärnberg, F., Casalini, P., Nordgren, H., Bergkvist, L., Holmberg, L., Ménard, S., 2002. Ductal carcinoma in situ of the breast: a new phenotype classification system and its relation to prognosis. Breast. Cancer. Res. Treat. 73, 215-222.

Welm, A.L., Sneddon, J.B., Taylor, C., Nuyten, D.S., van de Vijver, M.J., Hasegawa, B. H., Bishop, J.M., 2007. The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans. Proc. Natl. Acad. Sci. 104(18), 7570-7575.

Xu, F., Li, M., Zhang, C., Cui, J., Liu, J., Li, J., Jiang, H., 2017. Clinicopathological and prognostic significance of COX-2 immunohistochemical expression in breast cancer: a meta-analysis. Oncotarget. 8(4), 6003–6012.

Yamamoto, T., Ikawa, S., Akiyama, T., Semba, K., Nomura, N., Miyajima, N., Toyoshima, K., 1986. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature. 319(6050), 230-234.

Yamane, K., Kawabata, M., Tsuruo, T., 1997. A DNA‐Topoisomerase‐11–Binding Protein with Eight Repeating Regions Similar to DNA‐repair Enzymes and to a Cell‐Cycle Regulator. Eur. J. Biochem. 250(3), 794-799.

Yang, E., Zha, J., Jockel, J., Boise, L.H., Thompson, C.B., Korsmeyer, S.J., 1995. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 80(2), 285-291.

Yilmaz, E., Thomas, P.B., Tuna, B.G., Cleary, M.P., Dogan, S., 2022. Leptin receptors expression in mammary tumors and mammary fat pad of transgenic mammary cancer mouse model. Exp. Oncol. 44(4), 272-280.

Yu, H., Yang, J., Jiao, S., Li, Y., Zhang, W., Wang, J., 2015. Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: implications for prognosis. Cancer. Immunol. Immunother. 64, 853-860.

Zappulli, V., De Zan, G., Cardazzo, B., Bargelloni, L., Castagnaro, M., 2005. Feline mammary tumours in comparative oncology. J. Dairy. Res. 72(S1), 98-106.

Zappulli, V., Rasotto, R., Caliari, D., Mainenti, M., Peña, L., Goldschmidt, M.H., Kiupel, M., 2015. Prognostic evaluation of feline mammary carcinomas: a review of the literature. Vet. Pathol. 52(1), 46-60.

Zarychta, E., Ruszkowska-Ciastek, B., Bielawski, K., Rhone, P., 2021. Stromal cell-derived factor 1α (SDF-1α) in invasive breast cancer: associations with vasculo-angiogenic factors and prognostic significance. Cancers. 13(8), 1952.

Zeng, Y., Wang, X., Yin, B., Xia, G., Shen, Z., Gu, W., Wu, M., 2017. Role of the stromal cell derived factor-1/CXC chemokine receptor 4 axis in the invasion and metastasis of lung cancer and mechanism. J. Thorac. Dis. 9(12), 4947.

Zielińska, K.A., Katanaev, V.L., 2020. The signaling duo CXCL12 and CXCR4: Chemokine fuel for breast cancer tumorigenesis. Cancers. 12(10), 3071.

Zhang, Z., Ni, C., Chen, W., Wu, P., Wang, Z., Yin, J., Qiu, F., 2014. Expression of CXCR4 and breast cancer prognosis: a systematic review and meta-analysis. BMC cancer. 14, 1-8.

Zhou, W., Guo, S., Liu, M., Burow, M.E., Wang, G., 2019. Targeting CXCL12/CXCR4 axis in tumor immunotherapy. Curr. Med. Chem. 26(17), 3026-3041.

Zong, L., Mo, S., Yu, S., Zhou, Y., Zhang, M., Chen, J., Xiang, Y., 2020. Expression of the immune checkpoint VISTA in breast cancer. Cancer. Immunol. Immunother. 69(8), 1437-1446.