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1 Center for Translational Medicine, The First Affiliated Hospital, Xian Jiaotong University College of Medicine, 277 West Yanta Road, Xi an 710061, Shaanxi, People s Republic of China
The electronic version of this article is the complete one and can be found online at: http://www.jeccr.com/content/33/1/70 Received: 21 April 2014 Accepted: 18 August 2014 Published: 2 September 2014
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LKB1, also known as STK11 , is a master kinase that serves as an energy metabolic sensor and is involved in cell polarity regulation. Recent studies have indicated that LKB1 is related to breast tumorigenesis and breast cancer hills vet progression. However, little work has been done on the roles of LKB1 in cell polarity and epithelial-mesenchymal transition in breast cancer. In this study, we tried to prove that loss of LKB1 disrupts breast epithelial hills vet cell polarity and causes tumor metastasis and invasion. Methods
The relationships of LKB1 expression to clinic-pathological parameters and epithelial markers E-cadherin and high-molecular-weight -cytokeratin (HMW-CK) were investigated in 80 clinical breast cancer tissue samples and their paired normal control breast tissue samples by using immunohistochemistry. Then, the LKB1 expressions in metastatic and non-metastatic breast cancer cell lines were compared. The roles of LKB1 in cell polarity and epithelial-mesenchymal transition hills vet in breast cancer were determined by using immunofluorescence, western hills vet blot assay, and cell migration and invasive assays. Finally, the non-transformed human breast cell line MCF-10A was cultured in three dimensions to further reveal the role of LKB1 in breast epithelial cell polarity maintenance. Results hills vet
Histopathological analysis showed that LKB1 expression level was significantly negatively correlated with breast cancer TNM stage, and positively correlated with ER/PR status and expression levels hills vet of E-cadherin and HMW-CK. hills vet Immunofluorescence staining showed that LKB1 was co-localized with E-cadherin at adheren junctions. In vitro analysis revealed that loss of LKB1 expression enhanced migration, invasion and the acquisition of mesenchymal phenotype, while LKB1 overexpression in MDA-MB-435 s cells, which have a low basal level of LKB1 expression, promoted the acquisition of epithelial phenotype. Finally, it was found for the first time that endogenous hills vet LKB1 knockdown resulted in abnormal cell polarity in acini formed by non-transformed hills vet breast epithelial cells grown in 3D culture. Conclusion
Our data indicated that low expression of LKB1 was significantly associated with established markers of unfavorable breast cancer prognosis, such as loss of ER/PR, E-cadherin and HMW-CK. Knockdown of endogenous LKB1 gave rise to dysregulation of cell polarity and invasive phenotype of breast cancer cells. Keywords: LKB1; Breast cancer; Cell polarity; Metastasis; Invasion Introduction
The tumor suppressor gene LKB1, also known as serine/threonine protein kinase 11 (STK11 ), encodes a serine/threonine protein kinase that has multiple cellular functions, including tumor suppression, cell cycle regulation, and promotion of apoptosis. Germ line mutations of LKB1 give rise to Peutz-Jeghers Syndrome (PJS), a rare cancer susceptibility syndrome characterized by predisposition to gastrointestinal polyposis, mucocutaneous melanin pigmentation and multi-organ cancer susceptibility [ 1 ], [ 2 ]. LKB1 serves as a master kinase responsible for phosphorylation of the conserved threonine in the catalytic domains of 14 AMPK-related protein kinases (AMPKα1, hills vet AMPKα2, BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) [ 3 ]- [ 6 ]. AMPK is the most important downstream target of LKB1 and functions as a cellular energy sensor. Phosphorylation hills vet of AMPK will activate TSC1/TSC2, suppress the mTOR activity and dephosphorylate mTOR effectors S6K and 4E-BP1, which are involved in regulation of protein translation initiation [ 4 ], [ 7 ]. Thus, LKB1 regulates multiple biological pathways involved in cell growth and metabolism.
LKB1 also plays crucial