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Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion

BACKGROUND: 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 progression. However, little work has been done on the roles o...

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Autores principales: Li, Juan, Liu, Jie, Li, Pingping, Mao, Xiaona, Li, Wenjie, Yang, Jin, Liu, Peijun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431490/
https://www.ncbi.nlm.nih.gov/pubmed/25178656
http://dx.doi.org/10.1186/s13046-014-0070-0
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author Li, Juan
Liu, Jie
Li, Pingping
Mao, Xiaona
Li, Wenjie
Yang, Jin
Liu, Peijun
author_facet Li, Juan
Liu, Jie
Li, Pingping
Mao, Xiaona
Li, Wenjie
Yang, Jin
Liu, Peijun
author_sort Li, Juan
collection PubMed
description BACKGROUND: 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 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. 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 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. RESULTS: 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 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. 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.
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spelling pubmed-44314902015-05-15 Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion Li, Juan Liu, Jie Li, Pingping Mao, Xiaona Li, Wenjie Yang, Jin Liu, Peijun J Exp Clin Cancer Res Research BACKGROUND: 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 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. 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 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. RESULTS: 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 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. 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. BioMed Central 2014-09-02 /pmc/articles/PMC4431490/ /pubmed/25178656 http://dx.doi.org/10.1186/s13046-014-0070-0 Text en Copyright © 2014 Li et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Li, Juan
Liu, Jie
Li, Pingping
Mao, Xiaona
Li, Wenjie
Yang, Jin
Liu, Peijun
Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
title Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
title_full Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
title_fullStr Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
title_full_unstemmed Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
title_short Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
title_sort loss of lkb1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431490/
https://www.ncbi.nlm.nih.gov/pubmed/25178656
http://dx.doi.org/10.1186/s13046-014-0070-0
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