Abstract
Breast cancer is the most common invasive cancer in women worldwide, and can be subdivided into Luminal A, Luminal B, Her2, and Basal subtype (the PAM50 subtyping system). The lmo2 gene was traditionally recognized as a proto-oncogene in hematopoietic system but its functions in breast cancers remained largely unclear. Based on the Cancer Genome Atlas (TCGA) breast cancer dataset, herein we found that the significantly LMO2-correlated genes in normal or malignant samples were enriched in rather divergent cellular pathways, suggesting the function complexity of LMO2 in breast tissues. Moreover, high LMO2 expression level was found to predict a shorter patient survival in Luminal A type whereas a better outcome in Her2 type. Correspondingly, LMO2 also revealed function diversities in different PAM50 subtypes. In Luminal A type, the LMO2 related genes were primarily enriched in cancer-promoting pathways, including VEGF production, stemness, PPAR signal pathways, MAPK cascade and cell cycle regulation. In Her2 type however, the LMO2 related genes lacked the enrichment on most of the generally cancer-related pathways and were particularly enriched in negative regulation of ErbB pathway as well as MAPK cascade, suggesting a potentially anti-oncogenic role of LMO2 on this subtype. Taken together, this study drew a comprehensive overview of divergent functions of LMO2 on breast cancers, provided additional evidence for the function complexity of LMO2 in solid tumors and suggested the potential usage of LMO2 as a PAM50 subtype dependent biomarker for breast cancer clinic in the precision medicine era.
Highlights
The human lmo2 gene was first cloned from an acute T lymphocytic leukemia (T-ALL) patient in 1990 [1]
Based on the Cancer Genome Atlas (TCGA) breast cancer dataset, we found that the significantly LMO2-correlated genes in normal or malignant samples were enriched in rather divergent cellular pathways, suggesting the function complexity of LMO2 in breast tissues
Within the Cancer Genome Atlas (TCGA) breast invasive carcinoma RNA_seq dataset including 113 normal and 1095 primary malignant breast tissue samples, general statistical analysis revealed that the average LMO2 expression level (FPKM value) in normal tissues was significantly higher than any of the 4 subtypes of breast cancer (ANOVA followed by Tukey’s test, p < 0.001), while among the 4 subtypes, only a slight higher LMO2 expression was found in Luminal A type compared with Luminal B type (Tukey’s test, p < 0.001) or Her2 type (Tukey’s test, p = 0.002) (Figure 1A)
Summary
The human lmo gene was first cloned from an acute T lymphocytic leukemia (T-ALL) patient in 1990 [1]. Molecular function study of LMO2 revealed that it was widely expressed in a variety of tissue types [2, 3] and it located distinctively either in cytoplasm or in nucleus in different tissues [3]. As a nuclear transcriptional factor in hematopoietic-endothelial tissues, LMO2 primarily promoted embryonic hematopoiesis and angiogenesis [4,5,6], and triggers T cell leukemia when ectopically expressed in T cell progenitors [7,8,9]. In most of the epithelial normal and malignant tissues, LMO2 primarily located in cytoplasm [3]. The LMO2 protein consists of only two tandem LIM domains which mediate protein-proteins interactions [13], and no matter in cytoplasm or nucleus, it always acted as a bridge or blocker molecule in a variety of protein complexes [14,15,16,17,18]
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