Enhanced Expression of LKB1 in Breast Cancer Cells Attenuates Angiogenesis, Invasion, and Metastatic Potential

Abstract

LKB1 (also known as STK11) is a recently identified tumor suppressor gene whose mutation can lead to Peutz-Jeghers syndrome, which is characterized by gastrointestinal polyps and cancers of different organ systems. Approximately 30% of sporadic breast cancer samples express low levels of LKB1. This suggests that the LKB1 gene may be related to the tumorigenesis of breast cancer. We reintroduced LKB1 into MDA-MB-435 breast cancer cells that lack the LKB1 gene to investigate how overexpression of LKB1 affects tumor invasiveness and metastasis. Overexpression of the LKB1 protein in breast cancer cells resulted in significant inhibition of in vitro invasion. In vivo, LKB1 expression reduced tumor growth in the mammary fat pad, microvessel density, and lung metastasis. LKB1 overexpression was associated with down-regulation of matrix metalloproteinase-2, matrix metalloproteinase-9, vascular endothelial growth factor, and basic fibroblast growth factor mRNA and protein levels. Overexpression of the LKB1 protein in human breast cancer is significantly associated with a decrease in microvessel density. Our results indicate that LKB1 plays a negative regulatory role in human breast cancer, a finding that may lead to a new therapeutic strategy. (Mol Cancer Res 2006;4(11):843 -9)

Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization

“…Recent findings have also shown evidence that human LKB1 (PAR4) and its target AMPactivated protein kinase control polarity and assembly of tight junction structures in mammalian epithelial cells (13)(14)(15). LKB1 is also defined as a human tumor suppressor protein because germline Lkb1-inactivating mutations characterize Peutz-Jeghers cancer syndrome families, and, furthermore, somatic alterations or reduced gene expression of LKB1 are found in several carcinomas, including carcinomas of breast (16)(17)(18)(19)(20).…”

Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1

“…36 Similarly, another study on breast cancer has shown that LKB1 limits cancer cell abilities of metastasis and invasion by downregulating MMP-2 and MMP-9 protein. 37 Our study first found that LKB1 could promote the effect of cisplatin on inhibiting cell migration and invasion. To reveal the related mechanisms, we detected the expression levels of MMP-2 and MMP-9 proteins in different treated groups.…”

Expression of STK11 gene and its promoter activity in MCF control and cancer cells

“…Furthermore, under the stress, energy demand or energy supply imbalance conditions that are typical requirement of the tumor microenvironment leads to increase in the expression of AMPK that alters the cancer cell's flexibility to utilize nutrient glucose directly (Liang and Mills 2013;Herrmann et al 2011). Other studies reported that the knockdown of STK11 in MCF-7 and MDA-MB-435 cells induced migration and invasion of breast cancer cells due to which loss of cell polarity and cell-cell adhesion occurs (Li et al 2014;Zhuang et al 2006).…”