MMTV-like positive feline neoplasms: a deeper analysis of mammary carcinomas and new perspectives on lymphomas

Abstract The Mouse Mammary Tumor Virus (MMTV) causes mammary tumors in mice and has been implicated in the aetiology of murine lymphomas. The identification of MMTV-like sequences and antigens in human mammary carcinomas has suggested that a virus homologous to MMTV may be involved in human breast carcinomas cancerogenesis. Recently, a mouse mammary tumor virus-like (MMTV-like) is suspected to be involved in feline mammary carcinomas. The aim of this thesis was: (i) to investigate the presence of MMTV-like nucleotide sequences and viral protein in feline mammary carcinomas (FMCs) of different areas and feline lymphomas (FLs), and (ii) to characterize the molecular phenotype of the MMTV-like positive tumors. Our results showed that MMTV-like sequences were detected in 3/24 FMCs from Bologna (12.5%), in 6/86 FMCs from Pisa and in 5/53 FLs from Pisa (9.4%). The MMTV-like env sequences positive FMCs were six tubulopapillary carcinomas (three of grade II, two of grade I and one of grade III), one tubular carcinoma (grade II), one ductal carcinoma (grade II) and one solid carcinoma (grade III). The molecular phenotype of MMTV-like positive FMCs was basal-like for five tumors, luminal-like for three of them and luminal/basal-like for one. The MMTV-like env sequences positive FLs were three gastrointestinal lymphomas, one B-type diffuse large lymphoma, one B-type small non cleaved lymphoma, and one T-type diffuse mixed lymphoma; and two nasal lymphomas—both B-type lymphomas, one diffuse small cleaved lymphoma, and one diffuse mixed lymphoma. The correlation with the presence of the MMTV-like env nucleotide sequences and the localization of the lymphoid tumors in the nasal cavity resulted statistically significative. P14-staining expression was detected exclusively in the cytoplasm and nuclei of neoplastic mammary and lymphoid cells of PCR-positive samples. Multiple nucleotide alignment of the feline mammary MMTV-like env gene sequences showed sequence similarity ranging 98% to 100% to MMTV in 7 cases, while the other two presented some polymorphisms. Only little fragments of the target sequence were sequenced in positive lymphomas. The supplementary anamnesis collected from the referring clinicians and the owner of the MMTV-like-positive-lymphoma cats revealed that all the subjects had a history of contact with the external environment and/or catteries, and that two deceased subjects shared their environment with cats who also died of lymphoma. In conclusion, this thesis succeeds in demonstrating the presence of MMTV-like sequences and protein in FMCs, sampled in different geographic areas, and in FLs from Pisa. The characterization of the molecular phenotype of positive FMCs and FLs could contribute to understand the possible role of MMTV-like virus in tumor progression. The significative association between the presence of the viral sequences and the nasal localization of the lymphoid tumors, together with the data collected through the supplementary anamnesis, bring to the light aspects that should be further analyzed in order to understand the virus epidemiology.