PGC-1β cooperating with FOXA2 inhibits proliferation and migration of breast cancer cells

Abstract

Background: Breast 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. Methods: mRNA 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. Results: Our 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. Conclusions: We 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.

CD44 Promotes Breast Cancer Metastasis through AKT-Mediated Downregulation of Nuclear FOXA2

“…To investigate the downstream event of CD44, a human cancer stem cell RT 2 Profiler PCR Array was applied to MDA-MB-231 CD44 knockdown cells. We discovered that the mRNA levels of various genes were upregulated in CD44 knockdown cells, and we focused on FOXA2, which has been reported to inhibit epithelial to mesenchymal transition in breast cancer [ 24 , 25 , 45 ] ( Figure 2 a; Figure S2a ). Next, we confirmed our stem cell array results by Western blot ( Figure 2 b).…”

“…In another study, FOXA2 has been reported to inhibit mesenchymal transition in breast cancer through E-cadherin and ZEB-1 regulation [ 24 ]. Additionally, it has been found that FOXA2 interacts with other proteins to inhibit the proliferation and migration of breast cancer cells [ 25 , 45 ]. However, FOXA2 mRNA has also been reported to be associated with relapse in basal-like breast carcinoma [ 61 ].…”

miR-22-3p/PGC1β Suppresses Breast Cancer Cell Tumorigenesis via PPARγ

“…Previous experimental results have confirmed that PGC1β was significantly overexpressed in BC. Moreover, PGC1β could promote proliferation and migration while inhibiting the apoptosis of BC cells, suggesting it to have a tumor-promoter role in BC [20][21][22][23]. Several studies have shown that PPARγ is involved in inflammation, lipid metabolism, glucose homeostasis, and tumorigenesis [30,31].…”

“…FOX-O3/PGC1β signaling axis was proved essential to sustain the pancreatic ductal adenocarcinoma cancer stem cell properties [19]. Specifically, PGC1β was proved significantly overexpressed in BC and could inhibit the apoptosis of BC cells via the mTOR signaling pathway [20,21]. PGC1β regulates HER2-overexpressing BC cell proliferation by metabolic and redox pathways [22].…”

Association between PPARγ, PPARGC1A, and PPARGC1B genetic variants and susceptibility of gastric cancer in an Eastern Chinese population

“…They are well-established as master regulators of oxidative phosphorylation and fatty acid oxidation gene expression and are highly expressed in oxidative tissues such as brown adipose tissue, heart, kidney, skeletal muscle, and brain [19,20]. The PPARGC1 family has been reported to play an important role in cancer progression by promoting the expression of antioxidant genes, regulating the expression of vascular endothelial growth factor, and promoting glucose metabolism and adipogenesis [21][22][23]. Increased expression and activity of PPARGC1A in cancers of lung, prostate, cervical, breast, colon, and melanoma promoted cancer cell progression and chemoresistance [21,24].…”