Abstract
Oct-4 and Nanog in regulating the epithelial-mesenchymal transition (EMT) and metastasis of breast cancer has not been clarified. We found that both Oct-4 and Nanog expression were significantly associated with tumor pathology and poor prognosis in 126 breast cancer patients. Characterization of CD44+CD24-Cancer stem cell(CSC) derived from breast cancer cells indicated that CSC rapidly formed mammospheres and had potent tumorigenicity in vivo. Furthermore, TGF-β up-regulated the expression of Oct-4, Nanog, N-cadherin, vimentin, Slug, and Snail, but down-regulated E-cadherin and cytokeratin 18 expression, demonstrating that CSC underwent EMT. Knockdown of both Oct-4 and Nanog expression inhibited spontaneous changes in the expression of EMT-related genes, while induction of both Oct-4 and Nanog over-expression enhanced spontaneous changes in the expression of EMT-related genes in CSC. However, perturbing alternation of Oct-4 and Nanog expression also modulated TGF-β-induced EMT-related gene expression in CSC. Induction of Oct-4 and Nanog over-expression enhanced the invasiveness of CSC, but knockdown of both Oct-4 and Nanog inhibited the migration of CSC in vitro. Our data suggest that both Oct-4 and Nanog may serve as biomarkers for evaluating breast cancer prognosis. Our findings indicate that Oct-4 and Nanog positively regulate the EMT process, contributing to breast cancer metastasis.
Highlights
Breast cancer is the most common malignancy in women; currently, 115 million patients have breast cancer, resulting in 410,000 deaths annually worldwide [1]
Multivariate analysis indicated that lymph node metastasis and the molecular type of breast cancer (OR: 14.776; 95% CI: 3.386–64.477; p = 0.001) were independent factors associated with Oct-4 and Nanog co-expression (Table 3)
While there was no detectable Oct-4 and Nanog expression in non-tumor breast tissues, 41.27% of breast cancer samples were positive for Oct-4, 36.51% were positive Nanog, and 20% were positive for both Oct-4 and Nanog
Summary
Breast cancer is the most common malignancy in women; currently, 115 million patients have breast cancer, resulting in 410,000 deaths annually worldwide [1]. Increasing evidence has demonstrated that epithelial cancer cells undergo an epithelial-mesenchymal transition (EMT), which is essential in early-stage tumor metastasis [3]. CSC from mouse or human mammary glands or mammary carcinomas express EMT markers [6], www.impactjournals.com/oncotarget while immortalized mammary epithelial cells express EMT master regulators, such as Snail and Twist, and form mammospheres in vitro. CD133+CXCR4+ pancreatic CSC have EMT characteristics and invasiveness, which can be blocked by a CXCR4 inhibitor [8]. It is unclear how the EMT process is regulated in CSC during the development and progression of breast cancer
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