Obesity has a noteworthy role in breast tumor initiation and progression. Among the mechanisms proposed, the most validated is the development of chronic low-grade inflammation, supported by immune cell infiltration along with dysfunction in adipose tissue biology, characterized by an imbalance in adipocytokines secretion and alteration of their receptors within the tumor microenvironment. Many of these receptors belong to the seven-transmembrane receptor family, which are involved in physiological features, such as immune responses and metabolism, as well as in the development and progression of several malignancies, including breast cancer. These receptors are classified as canonical (G protein-coupled receptors, GPCRs) and atypical receptors, which fail to interact and activate G proteins. Among the atypical receptors, adiponectin receptors (AdipoRs) mediate the effect of adiponectin, the most abundant adipocytes-derived hormone, on breast cancer cell proliferation, whose serum levels are reduced in obesity. The adiponectin/AdipoRs axis is becoming increasingly important regarding its role in breast tumorigenesis and as a therapeutic target for breast cancer treatment. The objectives of this review are as follows: to point out the structural and functional differences between GPCRs and AdipoRs, and to focus on the effect of AdipoRs activation in the development and progression of obesity-dependent breast cancer.

In the breast tumor microenvironment (TME), adipocytes exert a selective pressure on the behavior of breast cancer stem cells (BCSCs), which are involved in endocrine therapy resistance. In obesity, adipocytes secrete reduced levels of adiponectin, which promotes the growth and progression of ERα-positive breast cancer (BC). Here, we examined how low adiponectin levels affect the enrichment of the BCSC subpopulation and the mechanisms contributing to the maintenance of endocrine therapy resistance in BC. Flow cytometry, qRT-PCR, and Western blotting analysis were performed to assess stemness, the cell cycle, and apoptosis markers in MCF-7 wild-type (WT) and tamoxifen-resistant (TR) mammospheres. nLC-MS/MS was employed to profile and compare the proteome of BCSCs. Differentially expressed proteins were intersected with data from the Metacore^TM dataset. Our study demonstrated that adiponectin increased the percentage of CD44⁺/CD24⁻/ALDH1⁺ stem-like cells in TR MCF-7 mammospheres. Specifically, adiponectin contributed to the maintenance of BCSC bulk in TR MCF-7 cells through a slow cycling rate, supported by decreased levels of Cyclin D1 and Ki67 and increased p21 and p27 expression, and through escape from apoptosis, sustained by reduced ROS production and preserved maintenance of mitochondrial membrane potential. Our results provide new insights into the contribution of adiponectin to poor ERα-positive BC outcomes. Deeply understanding adiponectin’s role in stemness may disclose novel therapeutic approaches to treat hormone-resistant obese BC patients.

Glioblastoma (GBM) is the most common malignant brain tumor, with a poor prognosis and low survival. Its treatment includes complete surgical resection followed by radiotherapy combined with temozolomide (TMZ). GBM contains glial stem cells (GSCs), which contribute to tumor progression, invasiveness, and drug resistance. The histone deacetylase (HDAC) inhibitor valproic acid (VA) has been shown to be a potent antitumor and cytostatic agent. In this study, we tested the effects of VA on glioma cell proliferation, migration, and apoptosis using T98G monolayer and spheroid cells. T98G and U-87MG glioblastoma cell viability was determined by MTT. Cell cycle and ROS levels were analyzed by flow cytometry, and gene and protein levels were detected, respectively, by RT-PCR and immunoblotting. VA reduces cell viability in 2D and 3D T98G and U-87MG cells and blocks the cell cycle at the G0/G1 with decreased levels of cyclin D1. VA addresses apoptosis and ROS production. In addition, VA significantly decreases the mRNA levels of the mesenchymal markers, and it counteracts cell migration, also decreasing MMP2. The results confirm the inhibitory effect of VA on the growth of the T98G and U-87MG cell lines and its ability to counteract migration in both 2D and 3D cellular models.

Glioblastoma (GBM) is an aggressive type of brain cancer, frequently invasive, with a low survival rate and complicated treatment. Recent studies have shown the modulation of epithelial–mesenchymal transition (EMT) biomarkers in glioblastoma cells associated with tumor progression, chemoresistance, and relapse after treatment. GBM handlings are based on aggressive chemical therapies and surgical resection with poor percentage of survival, boosting the search for more specific remedies. Marine eukaryotic microalgae are rapidly advancing as a source of anticancer drugs due to their ability to produce potent secondary metabolites with biological activity. Among such microalgae, dinoflagellates, belonging to the species Amphidinium carterae, are known producers of neurotoxins and cytotoxic compounds. We tested the capability of chemical extracts from two different strains of A. carterae to modulate the EMT markers in T98G, human GBM cells. In vitro proliferation and migration studies and EMT biomarkers’ abundance and modulation assays showed that the different A. carterae strains differently modulated both EMT markers and the proliferation/migration capability of GBM cells. This study sets the bases to find a marine microalgae-derived natural compound that could potentially target the epithelial–mesenchymal transition in brain-derived tumor types.