Abstract
BackgroundCancer stem cells (CSCs) are believed to promote the malignant transformation of breast cancer via multiple signaling pathways, including the Wnt/β-catenin pathway. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been identified as a CSC-associated Wnt-regulated target gene, but its clinical significance in the context of breast cancer remains elusive. Therefore, the purpose of this study was to investigate the clinical significance of the LGR5-β-catenin axis in breast cancer.MethodsBreast cancer tissue blocks from 126 patients were used to construct a tissue microarray (TMA). Histopathological and clinical data including age; tumor size; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) level; tumor grade; lymph node (LN) status; and survival were obtained from the cancer registry database and patients’ medical records. Tissue on the breast TMA was scored for LGR5 and β-catenin expression using semi-quantitative immunohistochemical (IHC) staining. We also analyzed LGR5 expression in cellular datasets available through ONCOMINE, a web-based cancer microarray database.ResultsImmunohistochemical staining revealed that 58 tumors (46%) exhibited high LGR5 expression, whereas 56 tumors (47%) displayed high β-catenin expression. High levels of LGR5 expression were significantly associated with tumor size (p = 0.002), LN metastasis status (p = 0.044), and triple-negative breast cancer (p = 0.029), consistent with our findings from the ONCOMINE database. In addition, we also found that β-catenin -expressing breast cancers were positive correlated with HER2 overexpression. Finally, with respect to clinical outcomes, patients with high levels of LGR5-β-catenin axis expression exhibited poorer relapse-free survival (RFS) compared to patients with low levels of LGR5-β-catenin axis expression (p = 0.027).ConclusionLGR5 overexpression was significantly associated with high T stage and LN metastasis status. High LGR5 expression was also associated with reduced RFS, indicating that LGR5 may represent a promising prognostic marker for breast cancer patients.
Highlights
Cancer stem cells (CSCs) are believed to promote the malignant transformation of breast cancer via multiple signaling pathways, including the Wnt/β-catenin pathway
We determined whether Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) expression was associated with clinicopathological tumor features, including age, tumor grade, tumor size, lymph node (LN) status, estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status
We found that tumor size ≥ 2 cm, LN metastasis, and Triple negative breast cancer (TNBC) were associated with high levels of LGR5 expression (p = 0.002, p = 0.044 and p = 0.029, respectively; Table 1)
Summary
Cancer stem cells (CSCs) are believed to promote the malignant transformation of breast cancer via multiple signaling pathways, including the Wnt/β-catenin pathway. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been identified as a CSC-associated Wnt-regulated target gene, but its clinical significance in the context of breast cancer remains elusive. Breast cancer originates from the epithelial cells of the mammary gland, and, in some cases, is thought to arise from putative cancer stem cells (CSCs) [4]. CSCs are believed to promote the malignant transformation of many cancer types, including breast cancer, in part via activation of the Wnt/β-catenin pathway. The CSC-associated marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been previously shown to promote breast cancer progression and CSC maintenance, in part through activation of Wnt/β-catenin signaling [5]. Little is known about the associations between LGR5 expression and breast cancer clinicopathological features
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