The role of CtBP1 and Metabolic Syndrome in miRNA profiles in Breast Neoplasms
Introduction. Breast cancer (BrCa) is characterized by malignant cell growth in the breast. It can be classified based on molecular markers including Her-2 and estrogen and progesterone receptors, placing it into distinct phenotypic classes with unique treatments and prognoses1. It is the 2nd leading cause of cancer in women2. Susceptibility increases with age, nulliparity, radiation exposure, and hormone replacement therapy. Its pathogenesis is multifactorial. Various studies have shown that BrCa is positively linked to metabolic syndrome (MeS), a cluster of risk factors including abdominal obesity, hypertension, hyperglycemia, high triglycerides, and low HDL levels3. Studies have shown that MeS increases the expression of C-terminal binding proteins (CtBPs)4. These proteins are essential pro-survival factors and have potential as therapeutic targets in oncogenesis5, 6. In recent years, studies also suggest that CtBPs, particularly CtBP1, may explain the link between MeS and BrCa, in part by modulating miRNAs that regulate cell growth4, 7. Some miRNAs may also suppress BrCa by repressing CtBP18, 9. These findings may suggest a way to potentially help prevent BrCa by targeting CtBP1 via miRNAs in at-risk patients with MeS. Methods. GeneChip miRNA 4.0 was hybridized to total RNA isolated from CtBP1 depleted or control xenograft tumors generated in mice with MeS and identify which miRNAs were regulated by CtBP14. Female nu/nu mice were chronically fed with control or high-fat diet and inoculated in the mammary fat pad with control or CtBP1-depleted cells. Xenograft samples were collected, RNA isolated, and gene expression determined by RT-qPCR. Reactome analysis using miRSystem was used to identify miRNAs crucial for BrCa development7. miRNA mimic cell viability screen entailing 35 miRNAs in MDA-MB-231 human BrCa cells was used. Real-time cell analyzer (RTCA) assay was done to elucidate the role of miR-644a in viability of these cells, those of other BrCa subtypes, and two normal breast cell lines. Microarray analysis was utilized to look at genes regulated by miR-644a8. Results. MeS induced miR-381-5p and miR-194-1-5p expression and CtBP1 was found to modulate these two miRNAs, among others. These two are associated with cell proliferation and BrCa progression, respectively7. Also, another miRNA (644a) induced apoptosis in cell lines with p53-wt; miR-644a directly targets the CtBP1 gene8. Conclusions. Studies have found specific miRNAs upregulated by MeS and modulated by CtBP1 that can lead to BrCa, including miR-381-5p and miR-194-1-5p. Other miRNAs, such as mi-R644a, have been identified as targeting CtBP1 as a mechanism to suppress BrCa. CtBP1 is an important molecular link between MeS and BrCa, and miRNA expression profiles are critical in this interplay.
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