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OBJECTIVES: Gut microbiota dysbiosis is among the risk factors for breast cancer development, together with genetic background and dietary habits. However, caloric restriction has been shown to remodel the gut microbiota and slow tumor growth. Here, we investigated whether the gut microbiota mediates the preventive effects of long-term chronic or intermittent caloric restriction on breast cancer predisposition. METHODS: 10-week-old transgenic breast cancer-prone mice were randomly assigned to dietary groups (ad libitum, chronic caloric restriction, and intermittent caloric restriction groups) and fed up to week 81. Stool samples were collected at weeks 10 (baseline), 17 (young), 49 (adult), and 81 (old). 16S rRNA gene sequencing was performed to identify the gut microbiota profile of the different groups. In order to investigate the breast cancer gut microbiota profile within genetically predisposed individuals regardless of diet, mammary tumor-bearing mice and mammary tumor-free but genetically prone mice were selected from the ad libitum group (n = 6). RESULTS: Intermittent caloric restriction increased the microbial diversity of adult mice and modified age-related compositional changes. A total of 13 genera were differentially abundant over time. Pathogenic Mycoplasma was enriched in the re-feeding period of the old intermittent caloric restriction group compared with baseline. Furthermore, mammary tumor-free mice showed shared gut microbiota characteristics with mammary tumor-bearing mice, suggesting an early link between genetic predisposition, gut microbiota, and breast cancer development. CONCLUSIONS: Our study revealed the role of gut microbes in the preventive effects of caloric restriction against breast cancer development, implying the significance of diet and microbiome interplay.

Asunto(s)

Neoplasias de la Mama , Restricción Calórica , Microbioma Gastrointestinal , Animales , Restricción Calórica/métodos , Ratones , Femenino , Neoplasias de la Mama/microbiología , Neoplasias de la Mama/prevención & control , Ratones Transgénicos , Predisposición Genética a la Enfermedad , Heces/microbiología , Disbiosis/microbiología , ARN Ribosómico 16S

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This study investigated serum extracellular vesicles (EVs) in bitches with mammary neoplasms, in order to understand their size, shape, and concentration, as well as their association with tumor malignancy. Thirty bitches were categorized into control (n = 10), mammary tumor grades I and II (GI, n = 13), and grade III (GII, n = 7). Serum was separated from blood collected during mastectomy, and EVs were isolated using size exclusion chromatography. The analysis revealed no significant differences in EV concentrations among groups, with similar concentrations for control, GI, and GII. Ninety-one proteins were identified in EV-enriched samples, with six showing varied abundance across groups. Notably, keratin 18 was highly abundant in GI, while sushi domain-containing protein, EvC ciliary subunit 2, and the joining chain of multimeric IgM and IgA were increased in GII. Additionally, protocadherin 17 and albumin were upregulated in both GI and GII. ROC curves identified potential biomarkers for differentiating tumor grades. Enrichment pathway analysis revealed AFP gene upregulation in the GI. Mass spectrometry proteomics data were deposited in Mendeley Data. The study provides valuable insights into serum EV characterization in bitches, suggesting keratin 18 and protocadherin 17 as potential biomarkers for canine mammary neoplasia, with implications for future diagnostic and therapeutic strategies.

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In order to explore the therapeutic effect of Resveratrol (Res)-activated Natural Killer (NK) cells on canine mammary tumors, this study employed a range of assays, including wound healing, colony formation, Transwell, flow cytometry, and Western blot experiments, to investigate the impact of Res-pretreated NK cells on canine mammary tumor cells in vitro. Additionally, a tumor-bearing mouse model was utilized to further analyze the therapeutic effects of Res-pretreated NK cells in vivo. The results showed that Res enhances the capacity of NK cells to induce apoptosis, pyroptosis, and ferroptosis in canine breast tumor cells, while also augmenting their influence on the migration, invasion, and epithelial-mesenchymal transition of these cells. Furthermore, pretreatment of NK cells with Res significantly amplified their inhibitory effect on breast tumor growth in vivo and promoted tumor tissue apoptosis. Additionally, Res enhanced the recruitment of NK cells to other immune cells in the body. In summary, Res has been shown to enhance the anti-breast-tumor effect of NK cells both in vitro and in vivo, offering a new avenue for optimizing immunotherapy for canine breast tumors.

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Hormone receptor-positive (HR+) breast cancer (BC) is the most common type of breast cancer among women worldwide, accounting for 70-80% of all invasive cases. Patients with HR+ BC are commonly treated with endocrine therapy, but intrinsic or acquired resistance is a frequent problem, making HR+ BC a focal point of intense research. Despite this, the malignancy still lacks adequate in vitro and in vivo models for the study of its initiation and progression as well as response and resistance to endocrine therapy. No mouse models that fully mimic the human disease are available, however rat mammary tumor models pose a promising alternative to overcome this limitation. Compared to mice, rats are more similar to humans in terms of mammary gland architecture, ductal origin of neoplastic lesions and hormone dependency status. Moreover, rats can develop spontaneous or induced mammary tumors that resemble human HR+ BC. To date, six different types of rat models of HR+ BC have been established. These include the spontaneous, carcinogen-induced, transplantation, hormone-induced, radiation-induced and genetically engineered rat mammary tumor models. Each model has distinct advantages, disadvantages and utility for studying HR+ BC. This review provides a comprehensive overview of all published models to date.

Asunto(s)

Neoplasias de la Mama , Modelos Animales de Enfermedad , Animales , Femenino , Ratas , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Receptores de Estrógenos/metabolismo

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[This corrects the article DOI: 10.3389/fvets.2023.1187271.].

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BACKGROUND: Canine mammary tumors (CMTs) in intact female dogs provide a natural model for investigating metastatic human cancers. Our prior research identified elevated expression of Anterior Gradient 2 (AGR2), a protein disulfide isomerase (PDI) primarily found in the endoplasmic reticulum (ER), in CMT tissues, highly associated with CMT progression. We further demonstrated that increased AGR2 expression actively influences the extracellular microenvironment, promoting chemotaxis in CMT cells. Unraveling the underlying mechanisms is crucial for assessing the potential of therapeutically targeting AGR2 as a strategy to inhibit a pro-metastatic microenvironment and impede tumor metastasis. METHODS: To identify the AGR2-modulated secretome, we employed proteomics analysis of the conditioned media (CM) from two CMT cell lines ectopically expressing AGR2, compared with corresponding vector-expressing controls. AGR2-regulated release of 14-3-3ε (gene: YWHAE) and α-actinin 4 (gene: ACTN4) was validated through ectopic expression, knockdown, and knockout of the AGR2 gene in CMT cells. Extracellular vesicles derived from CMT cells were isolated using either differential ultracentrifugation or size exclusion chromatography. The roles of 14-3-3ε and α-actinin 4 in the chemotaxis driven by the AGR2-modulated CM were investigated through gene knockdown, antibody-mediated interference, and recombinant protein supplement. Furthermore, the clinical relevance of the release of 14-3-3ε and α-actinin 4 was assessed using CMT tissue-immersed saline and sera from CMT-afflicted dogs. RESULTS: Proteomics analysis of the AGR2-modulated secretome revealed increased abundance in 14-3-3ε and α-actinin 4. Ectopic expression of AGR2 significantly increased the release of 14-3-3ε and α-actinin 4 in the CM. Conversely, knockdown or knockout of AGR2 expression remarkably reduced their release. Silencing 14-3-3ε or α-actinin 4 expression diminished the chemotaxis driven by AGR2-modulated CM. Furthermore, AGR2 controls the release of 14-3-3ε and α-actinin 4 primarily via non-vesicular routes, responding to the endoplasmic reticulum (ER) stress and autophagy activation. Knockout of AGR2 resulted in increased α-actinin 4 accumulation and impaired 14-3-3ε translocation in autophagosomes. Depletion of extracellular 14-3-3ε or α-actinin 4 reduced the chemotaxis driven by AGR2-modulated CM, whereas supplement with recombinant 14-3-3ε in the CM enhanced the CM-driven chemotaxis. Notably, elevated levels of 14-3-3ε or α-actinin 4 were observed in CMT tissue-immersed saline compared with paired non-tumor samples and in the sera of CMT dogs compared with healthy dogs. CONCLUSION: This study elucidates AGR2's pivotal role in orchestrating unconventional secretion of 14-3-3ε and α-actinin 4 from CMT cells, thereby contributing to paracrine-mediated chemotaxis. The insight into the intricate interplay between AGR2-involved ER stress, autophagy, and unconventional secretion provides a foundation for refining strategies aimed at impeding metastasis in both canine mammary tumors and potentially human cancers.

Asunto(s)

Proteínas 14-3-3 , Actinina , Autofagia , Quimiotaxis , Estrés del Retículo Endoplásmico , Neoplasias Mamarias Animales , Mucoproteínas , Animales , Perros , Proteínas 14-3-3/metabolismo , Proteínas 14-3-3/genética , Femenino , Actinina/metabolismo , Actinina/genética , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Línea Celular Tumoral , Quimiotaxis/genética , Autofagia/genética , Estrés del Retículo Endoplásmico/genética , Mucoproteínas/genética , Mucoproteínas/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas Oncogénicas/genética

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Over the past few decades, women have been troubled by grave diseases such as breast cancer, which are biologically and molecularly classified as hereditary diseases. Even though the risk of other cancers is relatively different and the downstream pathway of genetic mutation differs from breast cancer, the continued transformation of genes such as BRCA1 and BRCA2 leads to breast cancer malignancy. Notably at the molecular level, a parallel connection between the normal growth of breast and the progression of mammary cancer where the breast cancer stem cells play a crucial role in the advancement of mammary carcinoma. Arguably, several significant signaling pathways, for instance, ER signaling, HER2 signaling, and Wnt signaling control the typical breast development as well as breast stem cells, thereby cell proliferation, cell differentiation, and cell motility are involved. Incidentally, the Mouse Mammary Tumor Virus (MMTV) is notable among the unexplained viral components influenced by virus-corrupting mammary carcinomas. According to the genesis, MMTV proviral DNA is integrated into mammary epithelial cells, and genomic lymphoid cells during viral replication and triggers the progression of cellular oncogenesis. This overview reveals the deadliest theories on breast cancer, molecular mechanisms, and the MMTV transmission cycle. To establish prevention therapies that are both acceptable and efficacious, addressing apprehensions related to the toxicity of these interventions must be a preliminary hurdle to overcome.

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OBJECTIVE: To compare the effects of constant rate infusions (CRI) of fentanyl or dexmedetomidine, combined with lidocaine and ketamine, on cardiovascular response during surgery, sevoflurane requirement and postoperative pain in dogs undergoing mastectomy. STUDY DESIGN: Prospective, randomized, blinded, clinical trial. ANIMALS: A total of 29 female dogs with mammary tumors. METHODS: Premedication consisted of intramuscular acepromazine and morphine. General anesthesia was induced with intravenous propofol and maintained with sevoflurane. Dogs were randomized to be administered intravenous DLK [dexmedetomidine 1 µg kg-1 loading dose (LD) and 1 µg kg-1 hour-1; lidocaine 2 mg kg-1 LD and 3 mg kg-1 hour-1; ketamine 1 mg kg-1 LD and 0.6 mg kg-1 hour-1; n = 14] or FLK (fentanyl 5 µg kg-1 LD and 9 µg kg-1 hour-1; same doses of lidocaine and ketamine; n = 15) during anesthesia. Cardiorespiratory variables and end-tidal sevoflurane (Fe'Sevo) were recorded during surgery. The number of dogs administered ephedrine to treat arterial hypotension [mean arterial pressure (MAP) < 60 mmHg] was recorded. Meloxicam was administered to both groups. Postoperative pain and rescue analgesia requirement were assessed for 24 hours using the short form of the Glasgow Composite Measure Pain Scale. Data were compared using a mixed effects model or a Mann-Whitney test. RESULTS: More dogs required ephedrine in FLK than in DLK (67% versus 7%). Heart rate was not significantly different between groups, whereas lower values of MAP (p ≤ 0.01) and Fe'Sevo (p = 0.018) were observed in FLK than in DLK. Rescue analgesia was administered to 2/15 dogs in FLK and 0/14 dogs in DLK. CONCLUSIONS AND CLINICAL RELEVANCE: Based on the cardiovascular response during surgery, intraoperative infusions of FLK and DLK provided adequate antinociception. Infusion of DLK provided greater stability of blood pressure. Both protocols resulted in minimal need for additional analgesia within 24 hours postoperatively.

Asunto(s)

Dexmedetomidina , Enfermedades de los Perros , Fentanilo , Ketamina , Lidocaína , Mastectomía , Dolor Postoperatorio , Sevoflurano , Animales , Perros/cirugía , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacología , Femenino , Ketamina/administración & dosificación , Ketamina/farmacología , Dolor Postoperatorio/veterinaria , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Mastectomía/veterinaria , Sevoflurano/administración & dosificación , Sevoflurano/farmacología , Lidocaína/administración & dosificación , Lidocaína/farmacología , Fentanilo/administración & dosificación , Fentanilo/farmacología , Enfermedades de los Perros/cirugía , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/farmacología , Infusiones Intravenosas/veterinaria , Neoplasias Mamarias Animales/cirugía , Estudios Prospectivos , Anestésicos por Inhalación/administración & dosificación

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In recent years, many studies have focused their attention on the dog as a proper animal model for human cancer. In dogs, mammary tumors develop spontaneously, involving a complex interplay between tumor cells and the immune system and revealing several molecular and clinical similarities to human breast cancer. In this review, we summarized the major features of canine mammary tumor, risk factors, and the most important biomarkers used for diagnosis and treatment. Traditional therapy of mammary tumors in dogs includes surgery, which is the first choice, followed by chemotherapy, radiotherapy, or hormonal therapy. However, these therapeutic strategies may not always be sufficient on their own; advancements in understanding cancer mechanisms and the development of innovative treatments offer hope for improved outcomes for oncologic patients. There is still a growing interest in the use of personalized medicine, which should play an irreplaceable role in the research not only in human cancer therapy, but also in veterinary oncology. Moreover, immunotherapy may represent a novel and promising therapeutic option in canine mammary cancers. The study of novel therapeutic approaches is essential for future research in both human and veterinary oncology.

Asunto(s)

Neoplasias de la Mama , Enfermedades de los Perros , Neoplasias Mamarias Animales , Perros , Humanos , Animales , Femenino , Neoplasias Mamarias Animales/patología , Neoplasias de la Mama/patología , Biomarcadores , Inmunoterapia , Enfermedades de los Perros/patología

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Background: Mammary gland tumors are the most prevalent neoplasm in intact female dogs, and they are good natural models to study comparative oncology. Most canine mammary malignancies, as in women, are commonly refractory to conventional therapies and demand continuous new therapeutic approaches. Crotalus durissus terrificus, also called rattlesnake, has more than 60 different proteins in its venom with multiple pharmaceutical uses, such as antitumor, antiviral, and antimicrobial action. Crotoxin, a potent ß-neurotoxin formed by the junction of two subunits, a basic subunit (CB-PLA2) and an acidic subunit (crotapotin), has already been reported to have anticancer properties in different types of cancers. Methods: In this work, we describe the cytotoxic potential of crotoxin and its subunits compared to doxorubicin (drug of choice) in two canine mammary carcinoma cell lines. Results: Crotoxin, CB-PLA2, crotalic venom, and doxorubicin decreased cell viability and the ability to migrate in a dose-dependent manner, and crotapotin did not present an antitumoral effect. For all compounds, the predominant cell death mechanism was apoptosis. In addition, crotoxin did not show toxicity in normal canine mammary gland cells. Conclusion: Therefore, this work showed that crotoxin and CB-PLA2 had cytotoxic activity, migration inhibition, and pro-apoptotic potential in canine mammary gland carcinoma cell lines, making their possible use in cancer research.

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Background: Epidemiological investigations suggest that patients with heart failure have a higher incidence of cancer; however, the causal role of cardiac disease on cancer progression remains unclear. Objectives: This study aimed to investigate the impact and underlying mechanisms of myocardial infarction (MI)-induced heart failure on tumor cell growth. Methods: We generated a syngeneic mouse model by implanting mammary tumor-derived 4T1 cells into BALB/c mice with MI resulting from ligation of the left anterior descending artery. Results: Mice with MI exhibited increased tumor volume, tumor weight, and Ki67-positive proliferative cells in the tumor tissue compared with the sham-operated mice. Furthermore, RNA sequencing analysis in the tumor tissue revealed significant enrichment of pathways related to tumor progression, particularly the PI3K-AKT pathway in the MI mice. Upregulation of tropomyosin receptor kinase A (TRKA) phosphorylation, an upstream regulator of PI3K-AKT signaling, was observed in the tumor tissue of the MI mice. We also observed elevated levels of circulating nerve growth factor (NGF), a ligand of TRKA, and increased NGF expressions in the myocardium after MI. In in vitro experiments, NGF stimulation led to increased cell proliferation, as well as phosphorylation of TRKA and AKT. Notably, inhibition of TRKA by small interfering RNA or the chemical inhibitor GW441756 effectively blocked these effects. Administration of GW441756 resulted in the suppression of tumor volume and cell proliferation in the MI mice. Conclusions: Our study demonstrates that MI promotes mammary tumor growth through the NGF-TRKA pathway. Consequently, inhibiting TRKA could represent a therapeutic strategy for breast cancer patients concurrently experiencing heart failure after MI.

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Cancer is the leading cause of death in both humans and companion animals. Canine mammary tumor is an important disease with a high incidence and metastasis rate, and its poor prognosis remains a serious clinical challenge. C6 ceramide is a short-chain sphingolipid metabolite with powerful potential as a tumor suppressor. However, the specific impact of C6 ceramide on canine mammary cancer remains unclear. However, the effects of C6 ceramide in canine mammary cancer are still unclear. Therefore, we investigated the role of C6 ceramide in the progress of canine mammary cancer and explored its potential mechanism. C6 ceramide inhibited cell growth by regulating the cell cycle without involving apoptosis. Additionally, C6 ceramide inhibited the migration and invasion of CHMp cells. In vivo, C6 ceramide decreased tumor growth and metastasis in the lungs without side effects. Further investigation found that the knockdown of EGR3 expression led to a noticeable increase in proliferation and migration by upregulating the expressions of pJAK1 and pSTAT3, thus activating the JAK1/STAT3 signaling pathway. In conclusion, C6 ceramide inhibits canine mammary cancer growth and metastasis by targeting EGR3 through the regulation of the JAK1/STAT3 signaling pathway. This study implicates the mechanisms underlying the anti-tumor activity of C6 ceramide and demonstrates the potential of EGR3 as a novel target for treating canine mammary cancer.

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Doxorubicin (DOX) is commonly used in cancer treatment but associated with cardiotoxicity. Pyridoxamine (PM), a vitamin B6 derivative, could be a cardioprotectant. This study investigated the effect of PM on DOX cardiotoxicity and DOX antitumor effectiveness. Sprague Dawley rats were treated intravenously with DOX (2 mg/kg/week) or saline over eight weeks. Two other groups received PM via oral intake (1 g/L in water bottles) next to DOX or saline. Echocardiography was performed after eight weeks. PM treatment significantly attenuated the DOX-induced reduction in left ventricular ejection fraction (72 ± 2% vs. 58 ± 3% in DOX; p < 0.001) and increase in left ventricular end-systolic volume (0.24 ± 0.02 µL/cm2 vs. 0.38 ± 0.03 µL/cm2 in DOX; p < 0.0001). Additionally, LA7 tumor cells were exposed to DOX, PM, or DOX and PM for 24 h, 48 h, and 72 h. Cell viability, proliferation, cytotoxicity, and apoptosis were assessed. DOX significantly reduced LA7 cell viability and proliferation (p < 0.0001) and increased cytotoxicity (p < 0.05) and cleaved caspase-3 (p < 0.001). Concomitant PM treatment did not alter the DOX effect on LA7 cells. In conclusion, PM attenuated DOX-induced cardiomyopathy in vivo without affecting the antitumor effect of DOX in vitro, highlighting PM as a promising cardioprotectant for DOX-induced cardiotoxicity.

Asunto(s)

Cardiomiopatías , Neoplasias Mamarias Animales , Ratas , Animales , Piridoxamina , Cardiotoxicidad/tratamiento farmacológico , Volumen Sistólico , Ratas Sprague-Dawley , Función Ventricular Izquierda , Doxorrubicina/farmacología

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Programmed death ligand-1 (PD-L1) is highly expressed in a variety of cancer cells and suggests a poorer prognosis for patients. The natural compound isorhamnetin (ISO) shows promise in treating cancers and causing damage to canine mammary tumor (CMT) cells. We investigated the mechanism of ISO in reducing PD-L1 expression in CMT cells. Clustered, regularly interspaced short palindromic repeat-associated protein 9 (CRISPR/Cas9) was used to mediate CD274 knockout in U27 cells. Then, monoclonal cells were screened and cultured. Nucleotide sequencing and expression of PD-L1 were detected. Additionally, we examined cell migration, invasion, and damage. Immunofluorescent staining of PD-L1 was examined in U27 cells. The signaling pathways were measured by Western blotting. Murine xenotransplantation models and murine immunocompetent allograft mammary tumor models were established to evaluate the effect of ISO therapy. Expression of Ki-67, caspase3, and PD-L1 were analyzed by immunohistochemistry. A pull-down assay was used to explore which proteins could bind to ISO. Canine EGFR protein was purified and used to detect whether it directly binds to ISO using a surface plasmon resonance assay. ISO inhibited the EGFR-STAT3-PD-L1 signaling pathway and blocked cancer growth, significantly increasing the survival rate of healthy cells. The cell membrane receptor EGFR was identified as a direct target of ISO. ISO could be exploited as an antineoplastic treatment of CMT by targeting EGFR to suppress PD-L1 expression.

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Antígeno B7-H1 , Neoplasias de la Mama , Quercetina , Animales , Perros , Ratones , Antígeno B7-H1/genética , Receptores ErbB/genética , Ligandos , Quercetina/análogos & derivados , Transducción de Señal , Factor de Transcripción STAT3 , Neoplasias de la Mama/veterinaria

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BACKGROUND: Numerous studies have shown that photodynamic therapy (PDT) has a therapeutic effect on mammary tumor cells, with 5-aminolevulinic acid (5-ALA-HCL) being a commonly used photosensitizer for PDT. Feline mammary tumors (FMTs) are relatively common. However, the cytotoxic and antitumor effects of 5-ALA-PDT on FMTs have not been clarified. To this end, we evaluated the therapeutic effect of 5-ALA-PDT on FMTs through in vitro experiments using an FMT FKR cell line established for this study. METHODS: We performed 5-ALA-PDT in 2D-cultured FKR-A (adherent cells) and 3D-cultured FKR-S (spheroid cells) cells and performed a series of studies to evaluate the cell viability and determine the protoporphyrin IX (PpIX) content in the cells as well as the expression levels of mRNAs associated with PpIX production and release. An in vivo study was performed to assess the effectiveness of 5-ALA-PDT. RESULTS: There was a significant difference in the concentration of PpIX in FMT cells under different incubation culture modes (2D versus 3D culture). The concentration of PpIX in FMT cells was correlated with the differences in cell culture (2D and 3D) as well as the expression levels of genes such as PEPT1, PEPT2, FECH, and HO-1. CONCLUSIONS: In the in vitro study, 5-ALA-PDT had a stronger inhibitory effect on 3D-cultured FKR-S cells, which resemble the internal environment of organisms more closely. We also observed a significant inhibitory effect of 5-ALA-PDT on FMT cells in vivo. To our knowledge, this is the first study on 5-ALA-PDT for FMTs under both 2D and 3D conditions.

Asunto(s)

Ácido Aminolevulínico , Fotoquimioterapia , Ratones , Gatos , Animales , Ácido Aminolevulínico/farmacología , Fármacos Fotosensibilizantes/farmacología , Fotoquimioterapia/métodos , Línea Celular Tumoral , Supervivencia Celular

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Primary angiosarcoma of the breast is very rare and difficult to pathologically diagnose especially on core needle biopsy. Only 11 cases of breast primary angiosarcoma diagnosed on core needle biopsy have been reported in English literature of last 5 years. We reported a case of primary angiosarcoma of the breast diagnosed on core needle biopsy and summarized the useful morphological clues in literature which prompted the diagnosis of angiosarcoma. A 50-year-old woman presented with a palpable mass in her left breast for a year. She never received breast surgery or radiotherapy before. Microscopically, the core needle biopsy specimen displayed interanastomosing vascular spaces that dissected through the mammary stroma and adipose tissue. The vascular channels were mostly lined by a single layer of endothelial cells with a mild degree of nuclear atypia, whereas focally, the endothelia were multilayered, with tufting and formation of glomerulus-like structures. CD31, CD34, and ERG immunochemical stain highlighted the endothelial cells lining on the vascular spaces. The Ki67 index was about 10%, and MYC was negative. Primary angiosarcomas have significant overlaps of morphological features with benign and borderline vascular lesions. Anastomosing vascular spaces, cytologic atypia, endothelial mitotic activity, infiltration of glandular parenchyma, elevated Ki-67, and high cellularity are all useful clues to diagnose angiosarcomas. Among them, anastomosing vascular spaces with infiltrated growth pattern especially invasion into the breast intralobular stroma and adipose tissue was the most common character of angiosarcomas which alert the possibility of malignancy in core needle biopsy. However, an accurate diagnosis demands integration of various histological clues and multidisciplinary discussion.

Asunto(s)

Neoplasias de la Mama , Hemangiosarcoma , Femenino , Humanos , Persona de Mediana Edad , Hemangiosarcoma/diagnóstico , Células Endoteliales , Biopsia con Aguja Gruesa , Mama/cirugía

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Background: Mammary gland tumors are the most prevalent neoplasm in intact female dogs, and they are good natural models to study comparative oncology. Most canine mammary malignancies, as in women, are commonly refractory to conventional therapies and demand continuous new therapeutic approaches. Crotalus durissus terrificus, also called rattlesnake, has more than 60 different proteins in its venom with multiple pharmaceutical uses, such as antitumor, antiviral, and antimicrobial action. Crotoxin, a potent β-neurotoxin formed by the junction of two subunits, a basic subunit (CB-PLA2) and an acidic subunit (crotapotin), has already been reported to have anticancer properties in different types of cancers. Methods: In this work, we describe the cytotoxic potential of crotoxin and its subunits compared to doxorubicin (drug of choice) in two canine mammary carcinoma cell lines. Results: Crotoxin, CB-PLA2, crotalic venom, and doxorubicin decreased cell viability and the ability to migrate in a dose-dependent manner, and crotapotin did not present an antitumoral effect. For all compounds, the predominant cell death mechanism was apoptosis. In addition, crotoxin did not show toxicity in normal canine mammary gland cells. Conclusion: Therefore, this work showed that crotoxin and CB-PLA2 had cytotoxic activity, migration inhibition, and pro-apoptotic potential in canine mammary gland carcinoma cell lines, making their possible use in cancer research.

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Animales , Perros , Neoplasias Mamarias Animales , Crotalus cascavella , Crotoxina , Citotoxinas , Enfermedades de los Perros , Venenos Elapídicos

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Aquaporins (AQPs) are water channel proteins, and the expression of AQPs in carcinoma cells has received much attention over the last 15 years. In the veterinary field, however, little is known about the expression of AQPs. In the present study using immunohistochemistry, we examined the expression of AQP1, AQP3, and AQP5 in canine mammary gland carcinomas. The 27 samples comprised 10 grade I, 12 grade II, and 5 grade III samples (See Materials and Methods section for grade classification method). AQP1 was expressed in only 2 of the grade III carcinomas, and the expression was limited to spindle-shaped cells in the solid structure and on the outside of the solid mass. AQP3-positive cells were observed in 20 of 22 grade I and II samples. On the other hand, among grade III carcinomas, AQP3 was expressed only in spindle-shaped cells in 1 sample. AQP5 was expressed in all grade I and II carcinomas but not in the grade III tumors. In addition, enhanced expression of basolateral AQP3 and apical AQP5 was observed in lobular hyperplastic cells. These results suggest that the expression patterns of AQP3 and AQP5 can be of help for judging the grading of canine mammary tumors and that AQP1 is likely to be involved in metastasis. Moreover, AQP3 and AQP5 might be relevant to lactation in female dogs.

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Carcinoma , Enfermedades de los Perros , Animales , Femenino , Perros , Inmunohistoquímica , Lactancia , Carcinoma/veterinaria

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Quiste Mamario , Masculino , Humanos , Quiste Mamario/diagnóstico

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Canine mammary tumors (CMTs) are commonly observed in old and unspayed female dogs. Recently, dogs have been increasingly spaying at a young age to prevent mammary tumors. These CMTs require extensive local excision and exhibit a high probability of metastasis to the regional lymph nodes and lungs during malignancy. However, the molecular and biological mechanisms underlying CMT development have not been fully elucidated, and research in this area is limited. Therefore, in this study, we established new CMT cell lines by isolating cells from tumor tissues and investigated phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), a target for human breast cancer. PIK3CA mutations were observed at a similar loci as in the human PIK3CA gene in half of all canine samples. Furthermore, we investigated whether alpelisib, a PIK3CA inhibitor approved by the U.S. Food and Drug Administration for human breast cancer treatment, along with fulvestrant, is effective for CMT treatment. Alpelisib exerted stronger anticancer effects on cell lines with PIK3CA mutations than on the wild-type cell lines. In conclusion, we established new CMT cell lines with PIK3CA mutations and confirmed the efficacy of alpelisib for CMT treatment in vitro.