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.

Cancer drug resistance poses a significant challenge in oncology, primarily driven by cancer cell plasticity, which promotes tumor initiation, progression, metastasis, and therapeutic evasion in many different cancers. Breast cancers (BCs) are a prominent example of that, with an estimated 2.3 million new cases and 670,000 BC-related deaths registered worldwide annually. Triple-negative BC is especially challenging for treatments demonstrating particularly aggressive disease course, an early manifestation of metastatic disease, frequent drug-resistant cancer types, and poor individual outcomes. Although chemosensitizing agents have been developed, their clinical utility in oncology remains unproven. The mitogen-activated protein kinase (MAPK) pathway is considered a critical regulator of intracellular and extracellular signaling highly relevant for both — genetic and epigenetic modifications. Dysregulation of the MAPK signaling pathways plays a significant role in conferring chemoresistance in BC. Contextually, targeting the MAPK pathway represents a promising strategy for overcoming drug resistance and enhancing the therapeutic efficacy of anticancer agents in BC treatment. On the other hand, flavonoids, a prominent class of phytochemicals, are key modulators of MAPK signaling. Flavonoids interact with the ERK, JNK, p38, and ERK5 pathways of the MAPK signaling cascade and present a promising avenue for developing novel anti-cancer therapies and re-sensitizing agents for the treatment of BC. Compounds such as quercetin, kaempferol, genistein, luteolin, myricetin, EGCG, baicalein, baicalin, nobiletin, morin, delphinidin, acacetin, isorhamnetin, apigenin, silymarin, among others, have been identified as specific modulators of MAPK signaling, exerting complex downstream effects in BC cells increasing therewith drug efficacy and suppressing tumor growth and aggressivity. These properties reflect mechanisms of great clinical relevance to overcome therapeutic resistance in overall BC management. This article highlights corresponding mechanisms and provides clinically relevant illustrations in the framework of 3P medicine for primary (protection of individuals at high risk against health-to-disease transition) and secondary care (protection against metastatic BC progression). 3PM novelty makes good use of patient phenotyping and stratification, predictive multi-level diagnostics, and application of Artificial Intelligence (AI) tools to the individualized interpretation of big data — all proposed for cost-effective treatments tailored to individualized patient profiles with clear benefits to patients and advanced BC management.

Breast cancer (BC) treatment efficacy is often compromised by tumor cell plasticity and multidrug resistance of multi-factorial origin. Among emerging therapeutic agents, flavonoids - a structurally diverse group of naturally occurring polyphenols - have demonstrated a significant potential to modulate the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway, a key driver of oncogenic transformation, immune evasion, and therapeutic failure in BC. Notably, natural compounds, including but not restricted to apigenin, quercetin, naringenin, morin, luteolin, butein, xanthohumol, silibinin, baicalein, nobiletin, rosmanol, orientin, eriocitrin, breviscapine, 8-hydroxydaidzein, icariside I, cardamonin, epigallocatechin-3-gallate, fisetin, brutieridin, melitidin, isoliquiritigenin, and sophoraflavanone G, have been recognized as potent JAK-STAT modulators in BC models. Through targeted interference with this pathway, flavonoids exert pleiotropic antitumor effects - enhancing the efficacy of chemotherapeutic agents, suppressing cellular proliferation and invasion, and reducing tumor aggressiveness. Beyond JAK-STAT signaling, flavonoids also influence several additional therapy resistance-related mechanisms, including regulation of ATP-binding cassette (ABC) transporters, promotion of apoptosis, suppression of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), cell cycle arrest, mitochondrial autophagy and mitophagy modulation, as well as remodeling of the tumor microenvironment. This article provides a comprehensive overview of the molecular mechanisms by which flavonoids overcome therapeutic resistance in BC, focusing on JAK-STAT signaling modulation. The paper follows principles of Predictive, Preventive, and Personalized Medicine (3PM), promoting the paradigm shift from reactive to proactive medicine. Contextually, it underscores the importance of multidisciplinary research to elucidate flavonoid-specific mechanisms, identify predictive biomarker panels, and develop advanced delivery systems, integrates patient phenotyping, multi-level diagnostics, and AI-driven data interpretation to enable cost-effective primary and secondary prevention, and therapeutic algorithms tailored to personalised patient profiles improving therefore individual outcomes.

Cell cultivation has been one of the most popular methods in research for decades. Currently, scientists routinely use two-dimensional (2D) and three-dimensional (3D) cell cultures of commercially available cell lines and primary cultures to study cellular behaviour, responses to stimuli, and interactions with their environment in a controlled laboratory setting. In recent years, 3D cultivation has gained more attention in modern biomedical research, mainly due to its numerous advantages compared to 2D cultures. One of the main goals where 3D culture models are used is the investigation of tumour diseases, in both animals and humans. The ability to simulate the tumour microenvironment and design 3D masses allows us to monitor all the processes that take place in tumour tissue created not only from cell lines but directly from the patient’s tumour cells. One of the tumour types for which 3D culture methods are often used in research is the canine mammary gland tumour (CMT). The clinically similar profile of the CMT and breast tumours in humans makes the CMT a suitable model for studying the issue not only in animals but also in women.

Endometrial mesenchymal stem cells (eMSCs) are a novel and biologically potent source of multipotent stromal cells with potential beyond reproductive medicine. This study explored their phenotypic profile, trilineage differentiation, and the cytoprotective effects of their conditioned media (eMSCCM) on oxidatively stressed neonatal and adult chondrocytes. Canine eMSCs displayed typical fibroblast-like morphology and expressed high levels of mesenchymal surface markers CD29 and CD44, low hematopoietic markers CD34/CD45, and variable CD90, confirming a mesenchymal identity. Differentiation assays revealed osteogenic and chondrogenic differentiation, whereas adipogenic activity was limited. Using eMSCCM at 25% and 50% concentrations, chondrocyte viability was assessed after exposure to 200 µM H₂O₂. eMSCCM significantly enhanced the viability of H₂O₂-stressed chondrocytes in a dose-dependent manner, particularly at 50%, with marked effects at 24 and 48 h. Although metabolic activity declined at 72 h, the treated cells remained more metabolically active than untreated controls. These findings suggest that eMSCCM offers promising cytoprotective effects for cartilage-related oxidative stress conditions.