Increased regucalcin gene expression extends survival in breast cancer patients: Overexpression of regucalcin suppresses the proliferation and metastatic bone activity in MDA-MB-231 human breast cancer cells in vitro

Abstract

Abstract. Human breast cancer is highly metastatic to bone and drives bone turnover. Breast cancer metastases cause osteolytic lesions and skeletal damage that leads to bone fractures. Regucalcin, which plays a pivotal role as an inhibitor of signal transduction and transcription activity, has been suggested to act as a suppressor of human cancer. In the present study, we compared the clinical outcome between 44 breast cancer patients with higher regucalcin expression and 43 patients with lower regucalcin expression. Prolonged relapse-free survival was identified in the patients with increased regucalcin gene expression. We further demonstrated that overexpression of full length, but not alternatively spliced variants of regucalcin, induces G1 and G2/M phase cell cycle arrest, suppressing the proliferation of MDA-MB-231 cells, a commonly used in vitro model of human breast cancer that metastasize to bone causing osteolytic lesions. Overexpression of regucalcin was found to suppress multiple signaling pathways including Akt, MAP kinase and SAPK/JNK, and NF-κB p65 and β-catenin along with increased p53, a tumor suppressor, and decreased K-ras, c-fos and c-jun. Moreover, we found that co-culture of regucalcin-overexpressing MDA-MB-231 cells with mouse bone marrow cells prevented enhanced osteoclastogenesis and suppressed mineralization in mouse bone marrow cells in vitro. Taken together, the present study suggests that regucalcin may have important anticancer properties in human breast cancer patients. Mechanistically, these effects are likely mediated through suppression of multiple signaling pathways, upregulation of p53 and downregulation of oncogenes leading to anti-proliferative effects and reduced metastases to bone, a phenotype associated with poor clinical outcome.

Tetramethylpyrazine regulates breast cancer cell viability, migration, invasion and apoptosis by affecting the activity of Akt and caspase-3

“…Previous studies have indicated that the Akt signaling pathway is a key factor in the viability and migration of a number of types of tumor including colorectal (32), and prostate cancer (33), and glioblastoma (34) and osteosarcoma (35). Additionally, the Akt signaling pathway is an important regulator of breast cancer (36)(37)(38). Apoptosis disorders are an additional cause for the occurrence of breast cancer.…”

Affinity Proteomics Exploration of Melanoma Identifies Proteins in Serum with Associations to T-Stage and Recurrence

“…signal transduction, cell proliferation and apoptosis [34], [35]. In a very recent study, increased mRNA expression levels of RGN were associated to a prolonged relapse-free survival when analyzed in 87 breast cancer patients, which also contributed to the conclusion that RGN may exhibit anticancer properties in human breast cancer [36]. As later discussed for mRNA, our study showed low protein levels of RGN in skin tissue (of melanoma patients and non-disease individuals), which points towards RGN being a potential cancer-related systemic marker and not necessarily specific for malignant melanoma [37].…”

Prolonged survival of patients with colorectal cancer is associated with a higher regucalcin gene expression: Overexpression of regucalcin suppresses the growth of human colorectal carcinoma cells in�vitro

“…We have previously demonstrated that survival was prolonged in patients with pancreatic cancer (23), breast cancer (24), hepatocellular carcinoma (25) and lung cancer (26) who had a higher regucalcin expression in their tumor tissues as compared with those with a lower regucalcin expression. In support of these findings, the overexpression of regucalcin exerted repressive effects on the growth of human pancreatic cancer MIA PaCa-2 cells (23), MDA-MB-231 breast cancer cells (24), liver cancer HepG2 cells (25) and lung adenocarcinoma A549 cells (26) in vitro. Regucalcin may thus play a potential role as a suppressor of the development of carcinogenesis in human subjects, demonstrating its significance as a novel biomarker in the diagnosis of human cancer.…”

“…Importantly, regucalcin gene expression has been shown to be decreased in various tissues of human cancer (15,16,22), suggesting that a diminished regucalcin gene expression may induce the promotion of carcinogenesis (15,16,22). We have previously demonstrated that survival was prolonged in patients with pancreatic cancer (23), breast cancer (24), hepatocellular carcinoma (25) and lung cancer (26) who had a higher regucalcin expression in their tumor tissues as compared with those with a lower regucalcin expression. In support of these findings, the overexpression of regucalcin exerted repressive effects on the growth of human pancreatic cancer MIA PaCa-2 cells (23), MDA-MB-231 breast cancer cells (24), liver cancer HepG2 cells (25) and lung adenocarcinoma A549 cells (26) in vitro.…”