Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer.

Liver kinase B1 (LKB1) is a tumor suppressor gene identified in hereditary Peutz-Jeghers syndrome1. It is involved in the control of metabolism2 and tumorigenesis3. When LKB1 interacts with AMP-activated protein kinase (AMPK), it abrogates signal transduction through the mammalian target of rapamycin (mTOR) to inhibit cell growth4, thus functioning as a tumor suppressor2. In previous studies on breast cancer, reduced LKB1 expression was associated with increased metastatic and invasive potential5. Therefore, LKB1-related pathways might provide potential targets for mitigating the invasive and metastatic characteristics of breast cancer. A previous study evaluated LKB1 expression in metastatic estrogen receptor (ER)-positive breast cancer samples (n = 55) from the TAMRAD trial6,and observed that low LKB1 expression was predictive of everolimus efficacy. This study is the only human study to indicate the predictive value of LKB1 in targeted therapy for breast cancer. Other studies evaluating the role of LKB1 in breast cancer patients have provided inconsistent results. Two studies have evaluated the prognostic value of LKB1 in breast cancer patients. In Shen et al.7, low LKB1 expression was associated with low relapse-free survival (RFS) and overall survival (OS) in 116 breast cancer patients. By contrast, in Bouchekioua-Bouzaghou et al.8, high cytoplasmic LKB1 expression was associated with low disease-free survival (DFS) in a cohort of 154 breast cancer patients. In other studies, LKB1 status correlated with ER but in opposite directions. In a study on MCF-7 human breast cancer cells9, ERα downregulated LKB1 expression by regulating its promoter regions. In 2 human breast cancer studies, ER expression was associated with low LKB18 and high LKB15 expression. However, these studies have had relatively small samples (n = 154 and 80, respectively), thus limiting the ability to stratify patients into prognostic groups for LKB1 assessment. Nevertheless, the results have indicated that LKB1 might play a key role in breast cancer biology; therefore, its relationships with survival and ER status warrant further investigation. In this study, we investigated the role of LKB1 in breast cancer by evaluating LKB1 protein expression in 2 Asian cohorts using immunohistochemistry (IHC) stain, and by evaluating LKB1 gene expression in microarray data sets from 2 Western cohorts9. We analyzed the associations of LKB1 protein and gene expression with clinicopathologic factors, such as ER and human epidermal growth factor receptor 2 (HER2) statuses, and survival. We assessed the predictive value of LKB1 for survival outcomes according to various risk and prognostic groups.