Abstract
BackgroundLKB1, 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 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 cell polarity and causes tumor metastasis and invasion.MethodsThe 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 in breast cancer were determined by using immunofluorescence, western 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.ResultsHistopathological 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 of E-cadherin and HMW-CK. 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 LKB1 knockdown resulted in abnormal cell polarity in acini formed by non-transformed breast epithelial cells grown in 3D culture.ConclusionOur 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.
Highlights
The tumor suppressor gene Liver kinase B1 (LKB1), 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
LKB1 expression level was significantly negatively correlated with breast cancer stage and positively correlated with Estrogen receptor (ER)/Progesterone receptor (PR) status LKB1 expression levels in normal mammary and breast cancer tissues were determined by immunohistochemistry
Forty-five percent (17 cases) of stageII breast cancer showed moderately strong LKB1 staining while 51% (19 cases) had weak staining
Summary
The tumor suppressor gene LKB1, 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. LKB1 serves as a master kinase responsible for phosphorylation of the conserved threonine in the catalytic domains of 14 AMPK-related protein kinases (AMPKα1, AMPKα2, BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) [3,4,5,6]. AMPK is the most important downstream target of LKB1 and functions as a cellular energy sensor. LKB1, known as STK11, is a master kinase that serves as an energy metabolic sensor and is involved in cell polarity regulation. We tried to prove that loss of LKB1 disrupts breast epithelial cell polarity and causes tumor metastasis and invasion
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