Estrogen-related receptor α (ERRα) belongs to the superfamily of nuclear orphan receptors. However, the role of ERRα in bladder cancer remains unknown. This study examined the expression of ERRα in bladder cancer tissues and explored the molecular mechanisms of ERRα in bladder cancer progression. The expression of ERRα in bladder cancer tissues from 61 patients was determined by immunohistochemistry. We performed quantitative realtime polymerase chain reaction assay to detect the gene expression levels and carried out Western blot assay to measure protein levels. In vitro functional assays, including colony formation, Cell Counting Kit-8, Transwell invasion, and migration assays, were performed to detect bladder cancer cell growth, proliferation, invasion, and migration, respectively. Flow cytometry was used to determine the cell apoptotic rate of bladder cancer cells. Among the 61 detected bladder cancer tissues, 39 bladder cancer tissues showed positive ERRα immunoreactivity. Higher ERRα immunoreactivity score was significantly associated with TNM stage, tumor grade, distant metastasis, and poor survival in patients with bladder cancer. Univariate and multivariate analyses showed that ERRα immunoreactivity was an independent prognostic factor for overall survival in patients with bladder cancer. ERRα was found to be upregulated in bladder cancer cell lines, and knockdown of ERRα suppressed bladder cancer cell growth, proliferation, invasion, and migration; promoted bladder cancer cell apoptosis; and inhibited the epithelial-mesenchymal transition of bladder cancer cells. On the other hand, bladder cancer cell proliferation, invasion, and migration were significantly enhanced after cells were transfected with an ERRα-overexpressing vector. In vivo tumor growth and metastasis assays showed that ERRα knockdown resulted in remarkable inhibition of tumor growth and tumor metastasis in nude mice. Collectively, our results suggest that J Cell Biochem. 2019;120:13841-13852.wileyonlinelibrary.com/journal/jcb

Breast cancer is the most frequently diagnosed cancer in both more and less economically developed countries and remains the leading cause of cancer-related death in women worldwide. In this study, to explore the expression and pathological role of RSK4 in breast cancer progression, we demonstrated that RSK4 expression was significantly decreased in breast cancer cells and tissues, and the overexpression of RSK4 in MDA‑MB‑231 cells inhibited cell migration and invasion. In a mouse model experiment, overexpression of RSK4 in mice further confirmed its critical role in regulating breast cancer tumorigenicity. The regulatory role of RSK4 in breast cancer development was mediated by AKT and extracellular signal‑regulated kinase (ERK) signaling pathways and the expression of RSK4 was altered by DNA methylation in promoter regions. These results provide important insight into the role of RSK4 in cancerogenesis and may help to improve the prevention, diagnosis and treatment of breast cancer.

Estrogen (E2) receptor (ER) upregulation has been associated with tumor progression and is the most commonly used clinical biomarker in breast cancer. X-linked ribosomal S6 kinase 4 (RSK4) is downregulated in breast cancer and may act as a tumor suppressor gene. In order to understand the association between the ER and RSK4, the present study studied the effects of RSK4 on ER-positive (ER +) breast cancer cell function, and the effects of E2 on RSK4 function and RSK4 methylation. Furthermore, the disease-free survival of patients with breast cancer with RSK4 hypermethylation/hypomethylation was investigated to establish the link between RSK4 methylation on patient prognosis. The expression levels of RSK4 were increased and RSK4 promoter methylation was decreased in ER + breast cancer tissues and cell lines compared with ER-negative breast cancer tissues and cell lines, respectively. ER expression was negatively correlated with RSK4 expression and positively associated with RSK4 methylation. In vitro overexpression of RSK4 decreased the proliferation, clone formation, migration and angiogenesis and increased apoptosis of breast cancer cells. Patients with RSK4 hypomethylation exhibited a longer disease-free survival compared with patients with RSK4 hypermethylation. E2 stimulation of breast cancer cells increased ER expression and RSK4 methylation, which was associated with decreased RSK4 expression. Furthermore, ER upregulation was proposed to be related to the decreased expression of RSK4 in ER + breast cancer. E2 signaling may therefore act upstream of RSK4 to promote cancer progression. The results obtained in the current study suggested that RSK4 inhibited breast cancer cell invasiveness and that RSK4 promoter hypomethylation may serve as a novel prognostic marker for patients with breast cancer.

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Chinese tree shrew, an animal exhibited closer evolutionary relationship with humans compared to rodents, is getting increasingly attentions as an appealing experimental animal model for human diseases. However, a high-efficiency and stable method to establish tree shrew breast precancerous lesions model has not been clearly elucidated. Thus, the current study aimed to explore the way of establishing breast precancerous model in tree shrew and investigate the pathologic characteristics of induced breast precancerous lesions. The results indicated that 7,12-dimethylbenz(a)anthracene (DMBA) could induce breast lesions in tree shrews. However, comparing to DMBA alone, an addition of medroxyprogesterone acetate (MPA) to DMBA critically increased the rate of induced breast lesion in tree shrews. Half of induced breast lesions were intraductal papilloma and the others were atypical ductal hyperplasia. Induced lesions showed positive expression of estrogen receptor α (ERα), progesterone receptor (PR) and cytokeratin 5/6 (CK5/6), but negative expression of human epidermal growth factor receptor-2 (Her-2). The expression of B cell lymphoma-extra large (Bcl-xl) was significantly higher and the expression of B cell lymphoma 2 associated X protein (Bax) was significantly lower in the precancerous lesions (atypical ductal hyperplasia) compared to benign tumor (intraductal papilloma). These results suggest that DMBA is able to induce breast lesions in tree shrews. Combination of DMBA and MPA may be more effective to establish breast precancerous lesion tree shrew models. Tree shrew might be a promising animal model for studying the tumorogenesis of breast cancer.