Abstract
BackgroundBreast cancer is one of the most common malignancy among females from the worldwide cancer incidence statistics. Peroxisome gamma coactivator-1β (PGC-1β) has long been identified to be involved in this type of tumorigenesis. However, the mechanisms of PGC-1β in human breast cancer have not been fully understood and the function requires to be further elucidated.MethodsmRNA and protein expression of PGC-1β and FOXA2 in breast cancer tissues and cell lines were determined by qRT-PCR and Western Blotting, respectively. To further visualize the expression and localization of PGC-1β and FOXA2, immunochemistry and immunofluorescence staining methods were employed. The effect of PGC-1β and FOXA2 on cell proliferation and migration were evaluated by CCK8, clone formation, transwell and wound-healing assays, which has been done either with stable PGC-1β knockdown or FOXA2 overexpression in vitro. Xenografts model of nude mice were used to evaluate tumor growth in vivo. In addition, proteins expression of the PI3K-AKT-mTOR signaling pathway involved in the regulation of breast cancer were detected by Western Blotting.ResultsOur results showed that PGC-1β was upregulated and FOXA2 was downregulated in breast cancer tissues and cell lines. These two proteins can be interacted with each other to form the complex. Also, we found the combination of PGC-1β interference with FOXA2 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth in vivo. We further identified that PGC-1β and FOXA2 strongly correlated with the PI3K-AKT-mTOR signaling pathway, and they exerted their biological functions by activating this pathway.ConclusionsWe demonstrated that downregulation of PGC-1β combined with overexpression of FOXA2 obviously inhibited the function of breast cancer cells through regulating the PI3K-AKT-mTOR pathway.
Highlights
Breast cancer is one of the most common malignancy among females from the worldwide cancer incidence statistics
We identified that Peroxisome gamma coactivator-1β (PGC-1β) interacts with forkhead box protein A2 (FOXA2), and it synergizes with FOXA2 to inhibit the biological functions of breast cancer cells through regulating the PI3K-AKTmTOR signaling pathway
MCF-7 and MDA-MB-231 cells were transfected with overexpression plasmid (FOXA2) and interference plasmid to detect the cell proliferation and migration. a Cell growth was evaluated by CCK-8 assay. b In vitro proliferative ability of two cell lines were detected by clone formation assay. c Cell metastatic was assessed using Transwell assay. (MCF-7: original magnification ×200, scale bar = 50 μm; MDA-MB-231: original magnification ×40, scale bar = 200 μm). d In vitro migration ability were detected using scratch wound healing assay. *P < 0.05, **P < 0.01. ***P < 0.001
Summary
Breast cancer is one of the most common malignancy among females from the worldwide cancer incidence statistics. The members of PGC-1 family are multifunctional transcriptional co-regulators that take on “molecular switches” in many physiological and pathological processes [6]. They are highly expressed in oxidative capacity and energy demanding tissues, such as heart, brain, skeletal muscle and brown adipose tissue [7,8,9,10] and considered to be essential for many of exercise response in skeletal muscle [11]. It has been reported that PGC-1β was closely related to the tumor biological properties and cancer cells proliferation via metabolic and redox pathways [17]. We postulated the PGC-1β may play an important role in the development and progression of breast cancer
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