Search Results (205)

Breast cancer (BC) is a malignant tumor that develops in the mammary gland due to uncontrolled cell proliferation. Estrogen receptor (ER) signaling, mediated by 17β-estradiol (E2), plays a crucial role in regulating cell proliferation, differentiation, and survival. Specifically, the binding of E2 to the estrogen receptor alpha (ERα) increases cell proliferation. Conversely, selective estrogen receptor beta (ERβ) agonists inhibit cancer cell proliferation by suppressing the expression of oncogenes, making ERβ an important therapeutic target. Given the urgent need for targeted and effective therapies for BC, we implemented a strategy based on multicomplex pharmacophores modeling of ERβ (MPMERβ) and ERα (MPMERα), performing a virtual cross-screening of databases of clinically approved and experimental drugs to identify those with high affinity and stereoelectronic complementarity with the ERβ agonist pharmacophore hypothesis. The implementation of a chemoinformatic strategy enabled the identification of Sobetirome, Labetalol, and Procaterol as molecular hits on the ERβ pharmacophore map. Procaterol showed the most significant antiproliferative activity in vitro assays, with IC₅₀ values of 21.26 and 36.10 µM in MCF-7 and MDA-MB-231, respectively. It is imperative to note that these findings require experimental validation of the ERβ activation pathways to strengthen the possible therapeutic repurposing of the drugs selected through our in silico approach. Finally, this strategy not only facilitates drug repurposing under in silico simulation but also provides valuable information for the rational design of new drugs against BC. Full article

Mammary gland tumors are among the most common neoplasms in female dogs. Macrophages are believed to play an important role in tumor progression and metastasis. The aim of this study was to determine whether hemosiderin-laden macrophages (HLMs) may be involved in the development of metastatic lesions in regional lymph nodes. Forty-two cases of mammary gland cancers in female dogs and their regional lymph nodes were included in the analysis. The samples were divided into two groups based on the presence or absence of metastases. The sections were stained with hematoxylin and eosin (HE) and Prussian blue and were additionally subjected to immunohistochemical labeling using antibodies against pan-cytokeratin (Pan-CK) and Ki-67. In 20 cases, no metastatic changes were detected in the regional lymph node, whereas metastases were identified in 22 cases. A positive correlation was observed between the number of HLMs in the tumor stroma and the number of HLMs in the regional lymph node. Furthermore, a positive correlation was found between Ki-67 nuclear immunoreactivity in the mammary tumor and the number of HLMs present within its stroma. HLMs may represent a component of the tumor microenvironment that promotes cancer cell proliferation and potentially contributes to the propensity for metastasis formation in mammary tumors of female dogs. Full article

Mammary gland tumors (MGT) are the most common neoplasms in intact female dogs and represent the third most frequent tumor type in female cats. Imaging plays a central role in the diagnosis, staging, and follow-up of these neoplasms. This review summarizes the diagnostic imaging features of canine and feline MGT and the advantages and limitations of each modality. Radiography and computed tomography (CT) are mainly used to detect pulmonary and abdominal metastases, while ultrasonography provides key information about primary tumor size, margins, echogenicity, vascularization, and elasticity. Advanced ultrasound techniques, such as Doppler, contrast-enhanced ultrasonography (CEUS), and elastography, improve differentiation between benign and malignant lesions. Magnetic resonance imaging (MRI) offers excellent soft-tissue detail and can assist in preoperative planning, whereas nuclear medicine techniques, including scintigraphy and positron emission tomography (PET), allow functional assessment and the early detection of micrometastases. Although histopathology remains the diagnostic gold standard, imaging is indispensable for characterizing primary lesions, evaluating metastatic spread, guiding sampling, and monitoring therapeutic outcomes in small animal oncology. By integrating and comparing the main imaging modalities applied to canine and feline mammary tumors, this review underscores their complementary roles in improving diagnosis, staging, and therapeutic decision-making in small animal oncology. Full article

Reduced lactation after forced weaning induces a tumor-promoting environment in the mammary gland, triggering key regulatory nodes common to both post-lactation involution and breast cancer, including calpains and miRs. We investigated how lactation duration modulates these nodes using two murine models: short lactation (forced weaning) and prolonged lactation (spontaneous-weaning). Additionally, the role of inflammation in calpain regulation was assessed in forced-weaned NOS-2 knockout mice. Morphological and molecular analysis in mammary tissue included histochemical staining, qPCR, enzymatic activity, Western blot and miRNA-seq. Mammary gland involution after prolonged lactation resulted in milder inflammation, reduced cell death and tissue remodeling, and lower collagen deposition compared to short lactation. The expression, activity and function of calpain-2 was found to be more sensitive to the model of lactation and inflammatory environment compared to calpain-1. Even after full regression (28 days postpartum), prolonged lactation maintained lower calpain-2 levels and higher expression of tumor suppressors miR-10b and miR-143/145. These persistent molecular differences suggest spontaneous weaning as the optimal model for healthy mammary gland regression, whereas forced weaning sustains alterations in calpain-2 and regulatory miRs that may increase post-partum breast cancer risk. The potential long-term influence of lactation duration on breast cancer development warrants further consideration in both clinical and public health contexts. Full article

The objective of this study was to assess the prevalence and clinicopathological characteristics of tumors in dogs and cats in Lithuania. A total of 3525 routine diagnostic samples collected from 1 January 2020 to 1 July 2025 were microscopically examined and statistically analyzed. Tumor prevalence was slightly higher in dogs (59.2%, n = 1693) compared with cats (56.5%, n = 375). Mammary gland tumors, skin tumors, and sarcomas were the most common neoplasms in both species, although notable interspecies differences were identified. In particular, feline mammary carcinomas were more aggressive, and squamous cell carcinoma was significantly more frequent in cats. These findings are consistent with international epidemiological trends and highlight the importance of species-specific diagnostic and management strategies. Full article

Canine mammary tumors (CMTs) are among the most frequently diagnosed neoplasms in female dogs, with complex etiologies involving age, breed, body size, and reproductive status. This retrospective study analyzed 250 cases comprising 361 mammary tumors to evaluate demographic patterns, histopathological subtypes, and their topographical distribution. The majority of tumors (88.64%) were malignant, with complex carcinoma being the most common subtype (24%), followed by intraductal papillary carcinoma (14.95%). The mean age at diagnosis was 9.36 years, with 60.8% of cases occurring in dogs older than 8 years. Mixed-breed dogs were most frequently affected, followed by Bichon-type breeds and German Shepherds. Small-sized dogs (<10 kg) accounted for 43.5% of cases. Regarding the reproductive status, 35.6% of dogs were unspayed, while the remainder were either intact or had an undetermined status, reflecting regional spaying practices. A statistically significant association was identified between histological subtype and mammary gland location, revealing non-random, region-specific tumor distribution. Complex carcinomas were frequently located in the left canial abdominal mammary segment (L.A2), right canial abdominal mammary segment (R.A2), and left inguinal mammary segment (L.ING); mixed and tubular carcinomas were more prevalent in R.A2 and R.ING; and tubulopapillary carcinomas appeared predominantly in L.ING. While no significant overall association was found between tumor grade and gland location, grade III carcinomas showed a possible predilection for the left inguinal gland (L.INGH), indicating a regional tendency that warrants further investigation. These findings underscore the importance of anatomical factors in the development of CMTs and support the integration of gland-specific tumor patterns into diagnostic assessment and surgical decision-making. Full article

Background: Basal-like breast cancer (BLBC) is a highly aggressive molecular subtype characterized by the strong expression of a gene cluster found in the basal or outer epithelial layer of the adult mammary gland. Patients with BLBC typically face a poor prognosis, with a shorter disease-free period and overall survival. Methods: In this study, we explored the proteomic profiles of BLBC patients using publicly available data from two large cohorts of breast cancer patients. By integrating cluster analysis, predictive modeling, protein differential abundance expression, and network analysis, we identified and validated the presence of two distinct subgroups, characterized by 256 upregulated and 99 downregulated proteins. Results: We report the upregulation of spliceosome components, especially SNRPG and its partners (BUD13, CWC15, SNRNP70, ZMAT12), indicating altered splicing activity between TNBC subgroups. Collagen proteins (COL1A1, COL1A2, COL3A1, COL11A1) were associated with tumor progression and metastasis. Proteins in the CCT complex and microtubule-associated proteins (TUBA1C, TUBB) were linked to cytoskeletal structure and chemotherapy resistance. Aminoacyl-tRNA synthetases (DARS1, IARS1, KARS1) may also play a role in TNBC development. Conclusions: These findings suggest the existence of novel molecular signatures that could improve TNBC classification, prognosis, and potential therapeutic targeting. Full article

Macrophage-mediated inflammation is known to be involved in the epithelial–mesenchymal transition (EMT) of various types of cancer. This makes macrophage-derived inflammatory factors prime targets for the development of new treatments. This study uncovers the therapeutic potential and action mechanism of DAB-2-28, a small-molecule derived from para-aminobenzoic acid, in the treatment of breast cancer. The luminal MCF-7 and the triple-negative MDA-MB-231 cancer cell lines used in this study represent, respectively, breast cancers in which the differentiation states are related to the epithelial phenotype of the mammary gland and breast cancers expressing a highly aggressive mesenchymal phenotype. In MCF-7 cells, soluble factors from macrophage-conditioned media (CM-MØ) induce a characteristic morphology of mesenchymal cells with an upregulated expression of Snail1, a mesenchymal marker, as opposed to a decrease in the expression of E-cadherin, an epithelial marker. DAB-2-28 does not affect the differential expression of Snail1 and E-cadherin in response to CM-MØ, but negatively impacts other hallmarks of EMT by decreasing invasion and migration capacities, in addition to MMP9 expression and gelatinase activity, in both MCF-7 and MDA-MB-231 cells. Moreover, DAB-2-28 inhibits the phosphorylation of key pro-EMT transcriptional factors, such as NFκB, STAT3, SMAD2, CREB, and/or AKT proteins, in breast cancer cells exposed to different EMT inducers. Overall, our study provides evidence suggesting that inhibition of EMT initiation or maintenance is a key mechanism by which DAB-2-28 can exert anti-tumoral effects in breast cancer cells. Full article

Obesity and metabolic dysfunction are established risk factors for luminal breast cancer, yet current preclinical models inadequately recapitulate the complex metabolic and immune interactions driving tumorigenesis. To develop and characterize an immunocompetent rat model of luminal breast cancer induced by chronic exposure to a cafeteria diet mimicking Western obesogenic nutrition, female rats were fed a cafeteria diet or standard chow from weaning. Metabolic parameters, plasma biomarkers (including leptin, insulin, IGF-1, adiponectin, and estrone), mammary gland histology, tumor incidence, and gene expression profiles were longitudinally evaluated. Gene expression was assessed by PCR arrays and qPCR. A subgroup underwent dietary reversal to assess the reversibility of molecular alterations. Cafeteria diet induced significant obesity (mean weight 426.76 g vs. 263.09 g controls, p < 0.001) and increased leptin levels without altering insulin, IGF-1, or inflammatory markers. Histological analysis showed increased ductal ectasia and benign lesions, with earlier fibroadenoma and luminal carcinoma development in diet-fed rats. Tumors exhibited luminal phenotype, low Ki67, and elevated PAI-1 expression. Gene expression alterations were time point specific and revealed early downregulation of ID1 and COX2, followed by upregulation of MMP2, THBS1, TWIST1, and PAI-1. Short-term dietary reversal normalized several gene expression changes. Overall tumor incidence was modest (~12%), reflecting early tumor-promoting microenvironmental changes rather than aggressive carcinogenesis. This immunocompetent cafeteria diet rat model recapitulates key metabolic, histological, and molecular features of obesity-associated luminal breast cancer and offers a valuable platform for studying early tumorigenic mechanisms and prevention strategies without carcinogen-induced confounders. Full article

Deciphering the spatiotemporal distribution of bacteria during breast cancer progression may provide critical insights for developing bacterial-based therapeutic strategies. Using a murine breast cancer model, we longitudinally profiled the microbiota in breast tumor tissue, mammary gland, spleen, and cecal contents at 3-, 5-, and 7- weeks post-tumor implantation through 16S rRNA gene sequencing. Breast tumor progression was associated with lung metastasis and splenomegaly, accompanied by distinct tissue-specific microbial dynamics. While alpha diversity remained stable in tumors, mammary tissue, and cecal contents, it significantly increased in the spleen (p < 0.05). Longitudinal analysis revealed a progressive rise in Firmicutes and a decline in Proteobacteria abundance within tumors, mammary tissue, and cecum, whereas the spleen microbiota displayed unique phylum-level compositional shifts. Tissue- and time-dependent microbial signatures were identified at phylum, genus, and species levels during breast tumor progression. Strikingly, the spleen microbiota integrated nearly all genera enriched in other sites, suggesting its potential role as a microbial reservoir. Gut-associated genera (Lactobacillus, Desulfovibrio, Helicobacter) colonized both cecal contents and the spleen, with Lactobacillus consistently detected across all tissues, suggesting microbial translocation. The spleen exhibited uniquely elevated diversity and compositional shifts, potentially driving splenomegaly. These results delineated the trajectory of microbiota translocation and colonization, and demonstrated tissue-specific microbial redistribution during breast tumorigenesis, offering valuable implications for advancing microbiome-targeted cancer therapies. Full article

Here, the authors report the first case of a primary mast cell tumor originating from the inguinal lymph node in a nine-year-old intact female Maltese dog that had undergone a left ureteral stent, ureterotomy and splenectomy, and left-side mastectomy, including inguinal lymph node removal and ovariohysterectomy, in South Korea in May 2024. The splenic mass, mammary gland mass, and inguinal lymph node underwent histopathological examination, resulting in the diagnosis of nodular hyperplasia, grade 1 mammary complex carcinoma, and a mast cell tumor (MCT), respectively. To clarify the origin of the MCT from the inguinal lymph node, a computed tomography (CT) scan was performed. In addition, through a blood smear test, mast cell leukemia was ruled out. After CT scanning by veterinary radiologists and a biopsy of all possible masses, it was finally concluded that the MCT primarily originated from lymph nodes, which is extremely rare in dogs. The patient is recovering well as of February 2025, just 7 months after the first diagnosis, following surgery and 16 weeks of chemotherapy with a combination of prednisolone and vinblastine, considering the C-kit PCR results of the left inguinal lymph node after the surgical removal of the MCT. This report is significant for two reasons, firstly because of the rarity of MCTs originating from lymph nodes other than the skin and gastrointestinal organs, and secondly because the authors propose a hypothesis for the rarity of primary lymph node mast cell tumors and the correlation between mammary gland tumors and mast cell tumor growth based on a comparative literature review in humans, focusing on molecular mechanisms. Full article

Background: The principal function of mammary glands is to produce milk to nourish the newborn. Optimal lactation is controlled by various hormones, growth factors, and cytokines. Objectives: Using 3D cultures of primary mouse mammary epithelial cells, we explored the effects of T helper (Th)1 cytokines, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α on the structure and function of mammary cells as well as the underlying mechanism. Methods: Three-dimensional cultures of mammary cells were treated with IFN-γ/TNF-α, and milk protein expression and acinar structures were analyzed by immunoblotting and immunofluorescence microscopy. Results: Our results revealed that combined treatment with IFN-γ and TNF-α inhibits prolactin-induced STAT5 tyrosine phosphorylation and β-casein expression. These cytokines also disrupted the structure of mammary acini, resulting in smaller or no lumens, disordered cell arrangements, and multilayered cells in certain regions. Additionally, some cells became elongated rather than maintaining their usual cube-like shape. Since cell proliferation and death can modulate the structural organization of acini, we examined the influences of IFN-γ and TNF-α on these events. Combined cytokine treatment moderately increased cell proliferation and cell death. Notably, stimulation with IFN-γ and TNF-α induced the expression of inducible nitric oxide synthase (iNOS), and the inhibition of iNOS partially restored acinar morphology and β-casein expression, revealing a novel mechanism for cytokine-induced acinar disruption. Conclusions: When a Th1 cytokine milieu is dominant, such as during inflammation and infection, IFN-γ and TNF-α might cause mammary gland ductal occlusion and lactation insufficiency. Full article

Genistein, a natural isoflavone, exerts anticancer effects on human breast cancer cells by modulating the unfolded protein response (UPR). However, the effect of genistein on UPR in canine mammary gland tumor (CMT) cells remains unknown. The aim of the present study was to investigate the anticancer effects of genistein on CMT-U27 cells, focusing on the regulation of UPR-related pathways and the associated cell death mechanisms. CMT-U27 cells were treated with genistein. Cell viability, apoptosis, and UPR-related protein expression were analyzed using MTS assay, Annexin V-Propidium Iodide (PI) staining, Western blotting, and immunocytochemistry. Genistein treatment significantly reduced cell viability and induced apoptosis, accompanied by an increased Bcl-2-associated X (Bax) ratio of B-cell lymphoma-2 (Bcl-2) and cleaved caspase-8 and caspase-3. On regulation of the UPR system, genistein treatment showed a dual-function by enhancing the protein kinase R-like endoplasmic reticulum kinase (PERK) signaling while suppressing the inositol-requiring enzyme 1 alpha (IRE1α)–X-box-binding protein 1 (XBP1) axis. Furthermore, genistein downregulated estrogen receptor alpha (ERα), which may contribute to the inhibition of IRE1α signaling through a disrupted positive feedback loop. These findings suggested that genistein modulates the UPR to induce apoptosis in CMT-U27 cells, highlighting its potential as a therapeutic or adjuvant agent for CMTs. Full article

Mammary gland tumors in dogs are very common in clinical practice. Betulinic acid is currently a compound considered to have anticancer properties in human mammary tumors via nanoemulsions. In this study, betulinic acid nanoemulsions with a particle size of less than 300 nm were prepared. Biopsies were obtained from five female dogs with mammary tumors for histopathological analysis, confirming that two were tubular mammary carcinomas (MMTs, malignant) and three were complex mammary adenomas (BMTs, benign). The five female dogs were administered with a daily oral dose of nanoemulsion containing 5 mg/kg of betulinic acid for 30 days. Tumor size was measured every 7 days, and the response to treatment was assessed according to RECIST (Response Evaluation Criteria In Solid Tumors) standards. In one of the females with MMTs treated with the nanoemulsion, the tumor size was reduced by approximately 38%, while in the BMT female dogs, the nanoemulsion reduced the tumor size by 25.3%. It was concluded that oral administration of betulinic acid nanoemulsions reduced the size of canine mammary tumors. Experimental studies are still needed to further evaluate this preparation. Full article

STAT3 and STAT5 are two related transcription factors involved in normal mammary gland development and function. However, inappropriate activation of either STAT3 or STAT5 has been shown to play a role in breast cancer, where STAT3 is highly associated with aggressive tumors and STAT5 is associated with lower-grade and more differentiated tumors. As transcription factors, STAT3 and STAT5 transcriptionally regulate genes involved in proliferation, migration, and chemoresistance. Furthermore, STAT3 and STAT5 transcriptional activity can be modulated by several known cofactors, where these cofactors can influence how STAT3 and STAT5 interact with DNA and with other proteins, ultimately affecting transcriptional function. Interestingly, STAT3 and STAT5 share a subset of overlapping target genes and can compete for DNA binding of shared binding sites. These STATs have also been shown to have opposing effects on overlapping target gene expression, where gene expression is determined by the STAT protein occupying the promoter. This is particularly interesting since STAT5-driven breast tumors are molecularly distinct from STAT3-driven breast tumors. Furthermore, concurrent activation of STAT3 and STAT5 is associated with more favorable tumor types compared to tumors with activated STAT3 alone, suggesting that the relationship between these two STATs is critical. Developing a better understanding about the roles that STAT3 and STAT5 play in breast cancer will be important for successful treatment in the future. Full article