Tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) play crucial roles in the initiation and progression of tumors. TME is composed of various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as non-cellular components like extracellular matrix (ECM) proteins and soluble factors. These elements interact with tumor cells through a complex network of signaling pathways involving cytokines, growth factors, metabolites, and non-coding RNA-carrying exosomes. Hypoxic conditions within the TME further modulate these interactions, collectively influencing tumor growth, metastatic potential, and response to therapy. EMT represents a dynamic and reversible process where epithelial cells undergo phenotypic changes to adopt mesenchymal characteristics in several cancers, including breast cancers. This transformation enhances cell motility and imparts stem cell-like properties, which are closely associated with increased metastatic capability and resistance to conventional cancer treatments. Thus, understanding the crosstalk between the TME and EMT is essential for unraveling the underlying mechanisms of breast cancer metastasis and therapeutic resistance. This review uniquely examines the intricate interplay between the tumor TME and epithelial-mesenchymal transition EMT in driving breast cancer metastasis and treatment resistance. It explores the therapeutic potential of targeting the TME-EMT axis, specifically through CD73-TGF-β dual-blockade, to improve outcomes in triple-negative breast cancer. Additionally, it underscores new strategies to enhance immune checkpoint blockade (ICB) responses by modulating EMT, thereby offering innovative insights for more effective cancer treatment.

Introduction: Nuclear factor kappa (NF-κB) plays a key role in cancer cell proliferation; thus, small molecule inhibitors of NF-κB activity can effectively inhibit breast cancer (BC) progression. We have previously reported oxazine and piperazine-linked pyrimidines as novel anti-cancer agents that can suppress NF-κB activation in BC cells. Moreover, the TRX-01 compound, an oxazine-linked pyrimidine, inhibited MCF-7 cells at a concentration of 9.17 µM in the Alamar Blue assay.Methods: This work involved the analysis of frontier molecular orbitals, HOMO-LUMO interactions, and molecular electrostatic potential for the TRX-01 structure. Additionally, the TRX-01 compound was studied for cytotoxicity, and migration as well as invasion assays were performed on BC cells.Results: Finally, TRX-01 blocked the translocation of NF-κB from the cytoplasm to the nucleus in MCF-7 cells and reduced NF-κB and IκBα levels in a dose-dependent manner. It also suppressed migratory and invasive properties of BC cells.Conclusion: Overall, the data indicates that TRX-01 can function as a novel blocker of BC growth and metastasis by targeting NF-κB activation.

Primary hyperparathyroidism (PHPT) caused by ectopic parathyroid adenomas in the superior mediastinum is rare and often leads to surgical failure. We report a case of severe PHPT in a 50-year-old female presenting with lower limb weakness and bone pain. Laboratory tests revealed marked hypercalcemia (serum calcium 3.48 mmol/L) and extremely elevated parathyroid hormone (PTH) levels (1920 pg/mL). Preoperative imaging, including neck ultrasound and 99mTc-MIBI SPECT/CT, precisely localized the ectopic adenoma to the superior mediastinum at the T1 vertebral level, posterior to the trachea, rather than in conventional parathyroid regions. The patient underwent successful complete resection of the tumor via meticulous neck and superior mediastinal exploration. Postoperatively, PTH and serum calcium levels normalized rapidly. In patients with biochemically confirmed PHPT and negative imaging in classical locations, the value of accurate preoperative imaging is underscored by this case as is intraoperative imaging guided exploration.