Breast cancer (BrCa) remains a significant cause of cancer-related deaths among women. Metastatic breast cancer, in particular, poses a major challenge in oncology. Recent research has shed light on the connection between metabolic syndrome (MeS), a cluster of metabolic abnormalities, and the progression of breast cancer, particularly its metastatic potential. This article delves into the intricate relationship between MeS, C-terminal binding protein 1 (CTBP1), and breast cancer metastasis, highlighting potential therapeutic targets and strategies.
Metabolic Syndrome as a Risk Factor for Breast Cancer
Metabolic syndrome (MeS) is a cluster of pathophysiological disorders. According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, it includes factors such as elevated blood pressure (≥130/85 mm Hg), high triglycerides (≥150 mg/dL), abdominal obesity (waist circumference ≥35 inches in women), low high-density lipoprotein (HDL-C) levels (<50 mg/dL for women), and elevated fasting glucose (≥ 110 mg/dL). Studies suggest that MeS is a risk factor for BrCa, with a stronger association observed in post-menopausal women. Moreover, a retrospective study indicated a higher prevalence of MeS in triple-negative breast cancer (TNBC).
CTBP1: A Molecular Link Between Metabolic Syndrome and Breast Cancer
C-terminal binding protein 1 (CTBP1), a transcriptional co-repressor of tumor suppressor genes, emerges as a crucial molecular link between MeS and BrCa. CTBP1 is activated after dimerization produced by NAD+ or NADH binding. CTBP1 has been proposed as a metabolic cellular sensor since it shows a higher affinity for NADH (>100-fold) compared to NAD+. Previously, it was found that MeS increased postnatal development of mice mammary gland observed as an induction of terminal bulbs number and epithelial changes in mammary ducts with high expression of CTBP1 and CCND1 in MeS mice. CTBP1's activation is influenced by the cellular NAD+/NADH ratio, making it a metabolic sensor. Hyperactivation of CTBP1 by MeS has been shown to promote tumor growth in breast cancer models.
CTBP1's Role in Modulating Breast Cancer Cell Adhesion and Migration
Metastasis is still the main cause of death for BrCa patients, and around 30% of women with BrCa diagnosed at early stages will progress to metastatic stage. The study aimed to investigate the role of CTBP1 and MeS in BrCa metastasis using a MeS experimental model. In vitro studies have demonstrated that CTBP1 can modulate the adhesion and migration of triple-negative breast cancer cells. CTBP1 protein diminished adhesion while increased migration of triple negative BrCa cells. Depletion of CTBP1 in MDA-MB-231 cells increased cell adhesion, while overexpression of CTBP1 in 4T1 and Hs578T cells decreased adhesion. Furthermore, CTBP1 depletion reduced the migratory capabilities of MDA-MB-231 cells, while CTBP1 overexpression enhanced the migration of 4T1 cells.
Influence of CTBP1 and Metabolic Syndrome on Gene and miRNA Expression in Breast Cancer
To study the relevance of CTBP1 and MeS in BrCa progression, female nu/nu mice were chronically fed with control diet (CD) or high fat diet (HFD) and inoculated in the mammary fat pad (MFP) with CTBP1-depleted (shRNA CTBP1) or control (shRNA Scramble) MDA-MB-231 cells. Xenograft samples were collected for total RNA isolation and expression of genes involved in key processes for BrCa progression was determined by RT-qPCR. CTBP1 and MeS modulated the expression of multiple genes (ITGB4, ITGB6, PRSS2, COL17A1 and FABP4) and miRNAs (miR-378a-3p, miR-146a-5p, let-7e-3p, miR-381-5p, miR-194-5p, miR-494-3p) involved in BrCa progression of MDA-MB-231-derived xenografts.
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CTBP1 significantly modulated the expression of ITGB4 and PRSS2 genes, while MeS regulated COL17A1 and FABP4 expression. Additionally, MeS induced ITGB6 expression specifically in CTBP1-high expression xenografts, suggesting that CTBP1 activation by MeS could be critical for ITGB6 expression.
A cluster of miRNAs with relevant roles in cell proliferation (miR-378a-3p, miR-146a-5p and miR-381) and tumor progression (miR-378a-3p, miR-146a-5p, miR-381, miR-223-3p, miR-494-3p, miR-940, miR-433, miR-522 and miR-637) were identified. CTBP1 modulated miR-494-3p, miR-381-5p, miR-378a-3p, let-7e-3p, miR-194-1-5p and miR-146a-5p in MDA-MB-231-derived xenografts. Furthermore, MeS induced miR-381-5p and miR-194-1-5p expression.
Impact of CTBP1 and Metabolic Syndrome on Breast Cancer Metastasis in vivo
Experimental evidence demonstrates that MeS can promote breast cancer metastasis in vivo. MeS increased lung micrometastasis and liver neoplastic disease in mice. CTBP1 hyperactivation seems to be critical for MeS effect on BrCa metastasis since CTBP1 depletion completely impaired the detection of circulating tumor cells. Mice fed with a high-fat diet (HFD) exhibited an increased percentage of lung metastases and liver neoplastic disease compared to those on a control diet. Moreover, MeS mice inoculated with control cells developed micrometastasis bigger than other groups, suggesting that CTBP1 hyperactivation by MeS increase both development of metastasis and aggressiveness of secondary tumors. MeS also increased the amount of human breast cancer cells in the lungs, particularly in mice injected with cells expressing higher levels of CTBP1.
Clinical Implications and Therapeutic Potential
Even though BrCa mortality has been reduced over the last decade, metastatic BrCa is still one of the main causes of cancer death in women, being the improvement in the survival rates of patients with metastatic BrCa a major concern for public health. Once metastasis occurs, BrCa becomes a systemic disease and the 5-year survival rate decreases to 20%. The identification of CTBP1 as a key player in MeS-driven breast cancer progression opens avenues for targeted therapeutic interventions.
Strategies aimed at inhibiting CTBP1 activity or disrupting its interaction with other proteins may hold promise in preventing or slowing down breast cancer metastasis, particularly in patients with metabolic syndrome. Furthermore, addressing the metabolic abnormalities associated with MeS through lifestyle modifications or pharmacological interventions could also contribute to reducing the risk of breast cancer progression.
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