Metastasis-associated protein 1 (MTA1) is transferred by exosomes and contributes to the regulation of hypoxia and estrogen signaling in breast cancer cells.

BACKGROUND: Exosomes are small membrane-bound vesicles that contribute to tumor progression and metastasis by mediating cell-to-cell communication and modifying the tumor microenvironment at both local and distant sites. However, little is known about the predominant factors in exosomes that contribute to breast cancer (BC) progression. MTA1 is a transcriptional co-regulator that can act as both a co-activator and co-repressor to regulate pathways that contribute to cancer development. MTA1 is also one of the most up-regulated proteins in cancer, whose expression correlates with cancer progression, poor prognosis and increased metastatic potential. METHODS: We identified MTA1 in BC exosomes by antibody array and confirmed expression of exosome-MTA1 across five breast cancer cells lines. Ectopic expression of tdTomato-tagged MTA1 and exosome transfer were examined by fluorescent microscopy. CRISPR/Cas9 genetic engineering was implemented to knockout MTA1 in MCF7 and MDA-MB-231 breast cancer cells. Reporter assays were used to monitor hypoxia and estrogen receptor signaling regulation by exosome-MTA1 transfer. RESULTS: Ectopic overexpression of tdTomato-MTA1 in BC cell lines demonstrated exosome transfer of MTA1 to BC and vascular endothelial cells. MTA1 knockout in BC cells reduced cell proliferation and attenuated the hypoxic response in these cells, presumably through its co-repressor function, which could be rescued by the addition of exosomes containing MTA1. On the other hand, consistent with its co-activator function, estrogen receptor signaling was enhanced in MTA1 knockout cells and could be reversed by addition of MTA1-exosomes. Importantly, MTA1 knockout sensitized hormone receptor negative cells to 4-hydroxy tamoxifen treatment, which could be reversed by the addition of MTA1-exosomes. CONCLUSIONS: This is the first report showing that BC exosomes contain MTA1 and can transfer it to other cells resulting in changes to hypoxia and estrogen receptor signaling in the tumor microenvironment. These results, collectively, provide evidence suggesting that exosome-mediated transfer of MTA1 contributes to BC progression by modifying cellular responses to important signaling pathways and that exosome-MTA1 may be developed as a biomarker and therapeutic target for BC.

Changes in coronary plaque morphology in patients with acute coronary syndrome versus stable angina pectoris after initiation of statin therapy.

OBJECTIVES: The aim of this study was to examine coronary plaque morphology after initiation of statins and compare changes in plaque morphology in patients presenting with acute coronary syndrome (ACS) versus stable angina pectoris (SAP). BACKGROUND: ACS is associated with a pan-inflammatory state, and intraplaque features of inflammation correlate with coronary plaque progression. Statins have known anti-inflammatory properties that may contribute toward their beneficial cardiovascular effects. METHODS: Sixty-nine statin-naive patients (ACS, n=55; SAP, n=14) underwent baseline imaging with optical coherence tomography and intravascular ultrasound. Repeat imaging was performed at 6 and 12 months. A total of 97 nonculprit plaques were analyzed (ACS, n=74; SAP, n=23). RESULTS: Fibrous cap thickness increased in both ACS and SAP patients (all P<0.001 compared with the baseline); the ACS group showed greater percent change in fibrous cap thickness at 12 months (192.8±148.9% in ACS vs. 128.2±88.7% in SAP, P=0.018). The ACS group also showed a significant decrease in plaque microvessels (44.6% at baseline vs. 26.6% at 12 months, P=0.0386). CONCLUSION: Compared with patients with SAP, patients presenting with ACS show more favorable changes in plaque morphology after starting statin treatment. This supports a potential additive benefit of statins in the inflammatory state of ACS and reaffirms the clinical importance of statin therapy for coronary atherosclerosis.