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Simple Summary Prostatic diseases are important worldwide, being the prostate cancer (PC) the most common tumor in men. Among the factors associated with PC development, the preneoplastic lesions are well-recognized. Preneoplastic lesions are cellular morphological alterations, induced by different factors and present a potential to progression for PC. In this scenario, dogs are considered spontaneous models. Dogs naturally develops prostatic hyperplasia, preneoplastic lesions and PC. Among the preneoplastic lesions, the proliferative inflammatory atrophy (PIA) develops spontaneously in dogs. PIA is an epithelial lesion induced by prostatic chronic inflammation, leading to a proliferative atrophy of the prostate gland. Thus, this study aimed to perform a full PIA morphological, phenotypical and molecular characterization in dogs. After reviewing the archives of the veterinary pathology service, it was identified 171 dogs containing PIA in the prostate gland, and among the PC cases (N = 84), it was identified PIA lesions surrounding 60.7% of PC cases. Besides that, we identified loss of genes related to the maintenance of prostatic tissue and can predispose to malignant transformation. Moreover, mutations in androgen receptor gene were identified, demonstration alteration in DNA in PIA. Overall, these results support the hypothesis that PIA can be considered a preneoplastic lesion in canine prostate. Abstract Proliferative inflammatory atrophy (PIA) is an atrophic lesion of the prostate gland that occurs in men and dogs and is associated with a chronic inflammatory infiltrate. In this study, we retrospectively reviewed canine prostatic samples from intact dogs, identifying 50 normal prostates, 140 cases of prostatic hyperplasia, 171 cases of PIA, 84 with prostate cancer (PC), 14 with prostatic intraepithelial neoplasia (PIN) and 10 with bacterial prostatitis. PIA samples were then selected and classified according to the human classification. The presence of PIA lesions surrounding neoplastic areas was then evaluated to establish a morphological transition from normal to preneoplastic and neoplastic tissue. In addition, the expression of PTEN, P53, MDM2 and nuclear androgen receptor (AR) were analyzed in 20 normal samples and 20 PIA lesions by immunohistochemistry and qPCR. All PIA lesions showed variable degrees of mononuclear cell infiltration around the glands and simple atrophy was the most common histopathological feature. PIA was identified between normal glands and PC in 51 (61%) out of the 84 PC samples. PIA lesions were diffusely positive for molecular weight cytokeratin (HMWC). Decreased PTEN and AR gene and protein expression was found in PIA compared to normal samples. Overall, our results strongly suggest that PIA is a frequent lesion associated with PC. Additionally, this finding corroborates the hypothesis that in dogs, as is the case in humans, PIA is a pre neoplastic lesion that has the potential to progress into PC, indicating an alternative mechanism of prostate cancer development in dogs.

Made available in DSpace on 2021-06-25T10:55:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-02-25 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Rapamycin is an antifungal drug with antitumor activity and acts inhibiting the mTOR complex. Due to drug antitumor potential, the aim of this study was to evaluate its effect on a preclinical model of primary mammary gland tumors and their metastases from female dogs. Four cell lines from our cell bank, two from primary canine mammary tumors (UNESP-CM1, UNESP-CM60) and two metastases (UNESP-MM1, and UNESP-MM4) were cultured in vitro and investigated for rapamycin IC50. Then, cell lines were treated with rapamycin IC50 dose and mRNA and protein were extracted in treated and non-treated cells to perform AKT, mTOR, PTEN and 4EBP1 gene expression and global proteomics by mass spectrometry. MTT assay demonstrated rapamycin IC50 dose for all different tumor cells between 2 and 10 μM. RT-qPCR from cultured cells, control versus treated group and primary tumor cells versus metastatic tumor cells, did not shown statistical differences. In proteomics were found 273 proteins in all groups, and after data normalization 49 and 92 proteins were used for statistical analysis for comparisons between control versus rapamycin treatment groups, and metastasis versus primary tumor versus metastasis rapamycin versus primary tumor rapamycin, respectively. Considering the two statistical analysis, four proteins, phosphoglycerate mutase, malate dehydrogenase, l-lactate dehydrogenase and nucleolin were found in decreased abundance in the rapamycin group and they are related with cellular metabolic processes and enhanced tumor malignant behavior. Two proteins, dihydrolipoamide dehydrogenase and superoxide dismutase, also related with metabolic processes, were found in higher abundance in rapamycin group and are associated with apoptosis. The results suggested that rapamycin was able to inhibit cell growth of mammary gland tumor and metastatic tumors cells in vitro, however, concentrations needed to reach the IC50 were higher when compared to other studies. Department of Veterinary Surgery and Animal Reproduction School of Veterinary Medicine and Animal Science São Paulo State University-UNESP Department of Veterinary Clinic School of Veterinary Medicine and Animal Science São Paulo State University-UNESP Institute of Health Sciences Universidade Paulista-UNIP Department of Veterinary Surgery and Animal Reproduction School of Veterinary Medicine and Animal Science São Paulo State University-UNESP Department of Veterinary Clinic School of Veterinary Medicine and Animal Science São Paulo State University-UNESP CAPES: 001 FAPESP: 2019/24079-1 CNPq: 422139/2018-1