miR-877-5p as a Potential Link between Triple-Negative Breast Cancer Development and Metabolic Syndrome.

Metabolic syndrome (MS) is a risk factor for breast cancer (BC) that increases its aggressiveness and metastasis. The prevalence of MS is higher in triple-negative breast cancer (TNBC), which is the molecular subtype with the worst prognosis. The molecular mechanisms underlying this association have not been fully elucidated. MiRNAs are small, non-coding RNAs that regulate gene expression. Aberrant expression of miRNAs in both tissues and fluids are linked to several pathologies. The aim of this work was to identify circulating miRNAs in patients with alterations associated with MS (AAMS) that also impact on BC. Using microarray technology, we detected 23 miRNAs altered in the plasma of women with AAMS that modulate processes linked to cancer. We found that let-7b-5p and miR-28-3p were decreased in plasma from patients with AAMS and also in BC tumors, while miR-877-5p was increased. Interestingly, miR-877-5p expression was associated with lower patient survival, and its expression was higher in PAM50 basal-like BC tumors compared to the other molecular subtypes. Analyses from public databases revealed that miR-877-5p was also increased in plasma from BC patients compared to plasma from healthy donors. We identified IGF2 and TIMP3 as validated target genes of miR-877-5p whose expression was decreased in BC tissue and moreover, was negatively correlated with the levels of this miRNA in the tumors. Finally, a miRNA inhibitor against miR-877-5p diminished viability and tumor growth of the TNBC model 4T1. These results reveal that miR-877-5p inhibition could be a therapeutic option for the treatment of TNBC. Further studies are needed to investigate the role of this miRNA in TNBC progression.

Adipose tissue from metabolic syndrome mice induces an aberrant miRNA signature highly relevant in prostate cancer development.

Prostate cancer (PCa) remains an important public health concern in Western countries. Metabolic syndrome (MeS) is a cluster of pathophysiological disorders with increasing prevalence in the general population that is a risk factor for PCa. Several studies have determined that a crosstalk between white adipose tissue (WAT) and solid tumors favors cancer aggressiveness. In this work, our main goal was to investigate the interaction between WAT and PCa cells through microRNAs (miRNAs), in MeS mice. We developed a MeS-like disease model using C57BL/6J mice chronically fed with high-fat diet (HFD) that were inoculated with TRAMP-C1 PCa cells. A group of five miRNAs (mmu-miR-221-3p, 27a-3p, 34a-5p, 138-5p, and 146a-5p) were increased in gonadal WAT (gWAT), tumors, and plasma of MeS mice compared to control animals. Three of these five miRNAs were detected in the media from gWAT and TRAMP-C1 cell cocultures, and significantly increased in MeS context. More importantly, hsa-miR-221-3p, 146a-5p, and 27a-3p were increased in bloodstream of PCa patients compared to healthy donors. Using miRNA microarrays, we found that 121 miRNAs were differentially released to the coculture media between HFD-gWAT and tumor cells compared to control diet-gWAT and tumor cells. Target genes for the 66 most deregulated miRNAs were involved in common pathways, mainly related to fatty acid metabolism, ER protein processing, amino acid degradation, PI3K AKT signaling, and PCa. Our findings show for the first time a signature of five miRNAs as important players involved in the interaction between WAT and PCa in MeS mice. Further research will be necessary to track these miRNAs in the interaction between these tissues as well as their role in PCa patients with MeS.

CTBP1 depletion on prostate tumors deregulates miRNA/mRNA expression and impairs cancer progression in metabolic syndrome mice.

About 20% of prostate cancer (PCa) patients progress to metastatic disease. Metabolic syndrome (MeS) is a pathophysiological disorder that increases PCa risk and aggressiveness. C-terminal binding protein (CTBP1) is a transcriptional corepressor that is activated by high-fat diet (HFD). Previously, our group established a MeS/PCa mice model that identified CTBP1 as a novel link associating both diseases. Here, we integrated in vitro (prostate tumor cell lines) and in vivo (MeS/PCa NSG mice) models with molecular and cell biology techniques to investigate MeS/CTBP1 impact over PCa progression, particularly over cell adhesion, mRNA/miRNA expression and PCa spontaneous metastasis development. We found that CTBP1/MeS regulated expression of genes relevant to cell adhesion and PCa progression, such as cadherins, integrins, connexins, and miRNAs in PC3 xenografts. CTBP1 diminished PCa cell adhesion, membrane attachment to substrate and increased filopodia number by modulating gene expression to favor a mesenchymal phenotype. NSG mice fed with HFD and inoculated with CTBP1-depleted PC3 cells, showed a decreased number and size of lung metastases compared to control. Finally, CTBP1 and HFD reduce hsa-mir-30b-5p plasma levels in mice. This study uncovers for the first time the role of CTBP1/MeS in PCa progression and its molecular targets.

CTBP1/CYP19A1/estradiol axis together with adipose tissue impacts over prostate cancer growth associated to metabolic syndrome.

Metabolic syndrome (MeS) increases prostate cancer (PCa) risk and aggressiveness. C-terminal binding protein 1 (CTBP1) is a transcriptional co-repressor of tumor suppressor genes that is activated by low NAD+ /NADH ratio. Previously, our group established a MeS and PCa mice model that identified CTBP1 as a novel link associating both diseases. We found that CTBP1 controls the transcription of aromatase (CYP19A1), a key enzyme that converts androgens to estrogens. The aim of this work was to investigate the mechanism that explains CTBP1 as a link between MeS and PCa based on CYP19A1 and estrogen synthesis regulation using PCa cell lines, MeS/PCa mice and adipose co-culture systems. We found that CTBP1 and E1A binding protein p300 (EP300) bind to CYP19A1 promoter and downregulate its expression in PC3 cells. Estradiol, through estrogen receptor beta, released CTBP1 from CYP19A1 promoter triggering its transcription and modulating PCa cell proliferation. We generated NSG and C57BL/6J MeS mice by chronically feeding animals with high fat diet. In the NSG model, CTBP1 depleted PCa xenografts showed an increase in CYP19A1 expression with subsequent increment in intratumor estradiol concentrations. Additionally, in C57BL/6J mice, MeS induced hypertrophy, hyperplasia and inflammation of the white adipose tissue, which leads to a proinflammatory phenotype and increased serum estradiol concentration. Thus, MeS increased PCa growth and Ctbp1, Fabp4 and IL-6 expression levels. These results describe, for the first time, a novel CTBP1/CYP19A1/Estradiol axis that explains, in part, the mechanism for prostate tumor growth increase by MeS.