Expression of SCUBE2 and BCL2 Predicts Favorable Response in ERα Positive Breast Cancer.

BACKGROUND: The study aimed at evaluating steroid biomarker genes (ERα, PGR, ERß) and determining the expression level of estrogen-regulated genes (SCUB2 and BCL2) and growth factors receptors (HER2 and IGFR1) in cancer tissue samples obtained from Iranian patients with breast cancer. Moreover, relationships with clinicopathologic aspects of tumor and response to treatment were studied. METHODS: The current study was conducted on 246 breast tissue samples. The expression levels of these genes and their relationships with clinicopathologic aspects and treatment response were evaluated. RESULTS: Based on immunohistochemistry (IHC) results, 12% of the ER negative patients expressed ERα. Comparing the effects of ERα and coexpression of BCL2 and SCUBE2 on the survival of the patients demonstrated remarkably poorer survival in ERα positive, SCUBE2, and BCL2 negative groups in comparison with other patients, which was statistically significant in the log-rank analysis (P = 0.01). Evaluation of the effects of coexpression of HER2 and IGFR1 on patients' survival demonstrated a worse survival rate in patients with positive expression of both receptors, which was insignificant. CONCLUSION: Many studies suggest that PGR alone is not enough for the functional evaluation of ERα. Evaluation of the progesterone receptor expression as well as other genes such as BLC2, SCUBE2, and IGFR1, seems necessary to evaluate functionality.

Regulation of efferocytosis by caspase-dependent apoptotic cell death in atherosclerosis.

During the growing process of the atherosclerotic lesions, lipid-filled macrophage foam cells form, accumulate, and ultimately undergo apoptotic death. If the apoptotic foam cells are not timely removed, they may undergo secondary necrosis, and form a necrotic lipid core which renders the plaque unstable and susceptible to rupture. Therefore, the non-lipid-filled fellow macrophages, as the main phagocytic cells in atherosclerotic lesions, need to effectively remove the apoptotic foam cells. In general, in apoptotic macrophages, caspases are the central regulators of several key processes required for their efficient efferocytosis. The processes include the generation of "Find-Me" signals (such as adenosine triphosphate/uridine triphosphate, fractalkine, lysophosphatidylcholine, and sphingosine-1-phosphate) for the recruitment of viable macrophages, generation of the "Eat-Me" signals (for example, phosphatidylserine) for the engulfment process, and, finally, release of anti-inflammatory mediators (including transforming factor ß and interleukin-10) as a tolerance-enhancing and an anti-inflammatory response, and for the motile behavior of the apoptotic cell. The caspase-dependent mechanisms are operative also in apoptotic macrophages driving the atherogenesis. In this review, we explore the role of the molecular pathways related to the caspase-dependent events in efferocytosis in the context of atherosclerosis. Understanding of the molecular mechanisms of apoptotic cell death in atherosclerotic lesions is essential when searching for new leads to treat atherosclerosis.

Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis.

In atherosclerosis, macrophages in the arterial wall ingest plasma lipoprotein-derived lipids and become lipid-filled foam cells with a limited lifespan. Thus, efficient removal of apoptotic foam cells by efferocytic macrophages is vital to preventing the dying foam cells from forming a large necrotic lipid core, which, otherwise, would render the atherosclerotic plaque vulnerable to rupture and would cause clinical complications. Ca2+ plays a role in macrophage migration, survival, and foam cell generation. Importantly, in efferocytic macrophages, Ca2+ induces actin polymerization, thereby promoting the formation of a phagocytic cup necessary for efferocytosis. Moreover, in the efferocytic macrophages, Ca2+ enhances the secretion of anti-inflammatory cytokines. Various Ca2+ antagonists have been seminal for the demonstration of the role of Ca2+ in the multiple steps of efferocytosis by macrophages. Moreover, in vitro and in vivo experiments and clinical investigations have revealed the capability of Ca2+ antagonists in attenuating the development of atherosclerotic plaques by interfering with the deposition of lipids in macrophages and by reducing plaque calcification. However, the regulation of cellular Ca2+ fluxes in the processes of efferocytic clearance of apoptotic foam cells and in the extracellular calcification in atherosclerosis remains unknown. Here, we attempted to unravel the molecular links between Ca2+ and efferocytosis in atherosclerosis and to evaluate cellular Ca2+ fluxes as potential treatment targets in atherosclerotic cardiovascular diseases.