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Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis.

Mahauad-Fernandez WD, DeMali KA, Olivier AK, Okeoma CM - Breast Cancer Res. (2014)

Bottom Line: In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival.In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival.Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA, 52242-1109, USA. wadiedaniel-mahauadfernandez@uiowa.edu.

ABSTRACT

Introduction: Several innate immunity genes are overexpressed in human cancers and their roles remain controversial. Bone marrow stromal antigen 2 (BST-2) is one such gene whose role in cancer is not clear. BST-2 is a unique innate immunity gene with both antiviral and pro-tumor functions and therefore can serve as a paradigm for understanding the roles of other innate immunity genes in cancers.

Methods: Meta-analysis of tumors from breast cancer patients obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were evaluated for levels of BST-2 expression and for tumor aggressiveness. In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival. In vitro, we assessed the effect of carcinoma cell BST-2 knockdown and/or overexpression on adhesion, anchorage-independent growth, migration, and invasion.

Results: BST-2 in breast tumors and mammary cancer cells is a strong predictor of tumor size, tumor aggressiveness, and host survival. In humans, BST-2 mRNA is elevated in metastatic and invasive breast tumors. In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival. Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

Conclusions: BST-2 contributes to the emergence of neoplasia and malignant progression of breast cancer. Thus, BST-2 may (1) serve as a biomarker for aggressive breast cancers, and (2) be a novel target for breast cancer therapeutics.

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Related in: MedlinePlus

BST-2 mRNA is prevalent in highly aggressive tumors and associates with patients’ poor survival. (A) RNA-seq data (n = 100) of paired tumor versus normal breast tissues from The Cancer Genome Atlas (TCGA) breast-invasive carcinoma (BRCA) data portal presented as scatter plot and heat map show that BST-2 is significantly elevated in tumor tissues compared to matched normal breast tissues. (B) Levels of BST-2 in tumor tissues of patients bearing different subtypes of invasive breast carcinomas show that BST-2 is upregulated in different breast tumors subtypes with the exception of the basal subtype. (C) BST-2 expression in tumors from Uppsala (Sweden) breast cancer patients obtained from GSE4922 was segregated into three BST-2 expression levels (relative units): low = 6.0 to 7.5, intermediate = 7.5 to 9.0, and high = 9.0 to 11.0. (D) Tumor size in patients with low, intermediate, or high levels of BST-2 is shown. (E) BST-2 GeneChip Robust Multiarray Averaging (GC-RMA) signal scores from healthy, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tumor-bearing patients obtained from GSE21422. (F) BST-2 levels from normal, primary tumors (tumors), and metastatic tumors (metastatic) of patients bearing invasive breast cancer (TCGA). (G) Kaplan-Meier survival analysis using TCGA (BRCA) primary tumor samples segregated into high and low BST-2 levels show a significant link between low BST-2 and patient survival. The median overall survival (OS) time and the area under the curve (AUC) for each group are shown. (H) Mammary epithelial and stromal cells obtained from normal and invasive breast cancer patients (GSE10797) show elevated BST-2 expression in cancerous epithelial cells but not in cancerous stromal cells. In all panels, numbers correspond to P values. The relative units for BST-2 RNA levels acquired from TCGA and Gene Expression Omnibus (GEO) datasets are SEM-normalized and centralized log2(x + 1). Error bars represent standard deviations and significance was taken at P <0.01**. ns = not significant.
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Fig1: BST-2 mRNA is prevalent in highly aggressive tumors and associates with patients’ poor survival. (A) RNA-seq data (n = 100) of paired tumor versus normal breast tissues from The Cancer Genome Atlas (TCGA) breast-invasive carcinoma (BRCA) data portal presented as scatter plot and heat map show that BST-2 is significantly elevated in tumor tissues compared to matched normal breast tissues. (B) Levels of BST-2 in tumor tissues of patients bearing different subtypes of invasive breast carcinomas show that BST-2 is upregulated in different breast tumors subtypes with the exception of the basal subtype. (C) BST-2 expression in tumors from Uppsala (Sweden) breast cancer patients obtained from GSE4922 was segregated into three BST-2 expression levels (relative units): low = 6.0 to 7.5, intermediate = 7.5 to 9.0, and high = 9.0 to 11.0. (D) Tumor size in patients with low, intermediate, or high levels of BST-2 is shown. (E) BST-2 GeneChip Robust Multiarray Averaging (GC-RMA) signal scores from healthy, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tumor-bearing patients obtained from GSE21422. (F) BST-2 levels from normal, primary tumors (tumors), and metastatic tumors (metastatic) of patients bearing invasive breast cancer (TCGA). (G) Kaplan-Meier survival analysis using TCGA (BRCA) primary tumor samples segregated into high and low BST-2 levels show a significant link between low BST-2 and patient survival. The median overall survival (OS) time and the area under the curve (AUC) for each group are shown. (H) Mammary epithelial and stromal cells obtained from normal and invasive breast cancer patients (GSE10797) show elevated BST-2 expression in cancerous epithelial cells but not in cancerous stromal cells. In all panels, numbers correspond to P values. The relative units for BST-2 RNA levels acquired from TCGA and Gene Expression Omnibus (GEO) datasets are SEM-normalized and centralized log2(x + 1). Error bars represent standard deviations and significance was taken at P <0.01**. ns = not significant.

Mentions: Meta-analysis of large-scale human breast cancer data from the GEO and TCGA was used to assess the level of BST-2 mRNA in breast tumors. We compared BST-2 expression in paired normal breast tissues versus resected BRCAs from subjects with known clinical outcomes. BST-2 expression was significantly higher in tumor tissues compared to their paired normal breast tissues (Figure 1A). Stratification of TCGA data into different tumor subtypes showed that compared to normal tissues, BST-2 expression was significantly elevated in all tumor subtypes analyzed with the exception of the basal subtype, where the difference did not reach statistical significance (Figure 1B). Of note, the high-grade luminal B tumors expressed more BST-2 mRNA than the low-grade luminal A, human epidermal growth factor receptor 2 (HER2)+, and basal type (Figure 1B).Figure 1


Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis.

Mahauad-Fernandez WD, DeMali KA, Olivier AK, Okeoma CM - Breast Cancer Res. (2014)

BST-2 mRNA is prevalent in highly aggressive tumors and associates with patients’ poor survival. (A) RNA-seq data (n = 100) of paired tumor versus normal breast tissues from The Cancer Genome Atlas (TCGA) breast-invasive carcinoma (BRCA) data portal presented as scatter plot and heat map show that BST-2 is significantly elevated in tumor tissues compared to matched normal breast tissues. (B) Levels of BST-2 in tumor tissues of patients bearing different subtypes of invasive breast carcinomas show that BST-2 is upregulated in different breast tumors subtypes with the exception of the basal subtype. (C) BST-2 expression in tumors from Uppsala (Sweden) breast cancer patients obtained from GSE4922 was segregated into three BST-2 expression levels (relative units): low = 6.0 to 7.5, intermediate = 7.5 to 9.0, and high = 9.0 to 11.0. (D) Tumor size in patients with low, intermediate, or high levels of BST-2 is shown. (E) BST-2 GeneChip Robust Multiarray Averaging (GC-RMA) signal scores from healthy, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tumor-bearing patients obtained from GSE21422. (F) BST-2 levels from normal, primary tumors (tumors), and metastatic tumors (metastatic) of patients bearing invasive breast cancer (TCGA). (G) Kaplan-Meier survival analysis using TCGA (BRCA) primary tumor samples segregated into high and low BST-2 levels show a significant link between low BST-2 and patient survival. The median overall survival (OS) time and the area under the curve (AUC) for each group are shown. (H) Mammary epithelial and stromal cells obtained from normal and invasive breast cancer patients (GSE10797) show elevated BST-2 expression in cancerous epithelial cells but not in cancerous stromal cells. In all panels, numbers correspond to P values. The relative units for BST-2 RNA levels acquired from TCGA and Gene Expression Omnibus (GEO) datasets are SEM-normalized and centralized log2(x + 1). Error bars represent standard deviations and significance was taken at P <0.01**. ns = not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4308845&req=5

Fig1: BST-2 mRNA is prevalent in highly aggressive tumors and associates with patients’ poor survival. (A) RNA-seq data (n = 100) of paired tumor versus normal breast tissues from The Cancer Genome Atlas (TCGA) breast-invasive carcinoma (BRCA) data portal presented as scatter plot and heat map show that BST-2 is significantly elevated in tumor tissues compared to matched normal breast tissues. (B) Levels of BST-2 in tumor tissues of patients bearing different subtypes of invasive breast carcinomas show that BST-2 is upregulated in different breast tumors subtypes with the exception of the basal subtype. (C) BST-2 expression in tumors from Uppsala (Sweden) breast cancer patients obtained from GSE4922 was segregated into three BST-2 expression levels (relative units): low = 6.0 to 7.5, intermediate = 7.5 to 9.0, and high = 9.0 to 11.0. (D) Tumor size in patients with low, intermediate, or high levels of BST-2 is shown. (E) BST-2 GeneChip Robust Multiarray Averaging (GC-RMA) signal scores from healthy, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tumor-bearing patients obtained from GSE21422. (F) BST-2 levels from normal, primary tumors (tumors), and metastatic tumors (metastatic) of patients bearing invasive breast cancer (TCGA). (G) Kaplan-Meier survival analysis using TCGA (BRCA) primary tumor samples segregated into high and low BST-2 levels show a significant link between low BST-2 and patient survival. The median overall survival (OS) time and the area under the curve (AUC) for each group are shown. (H) Mammary epithelial and stromal cells obtained from normal and invasive breast cancer patients (GSE10797) show elevated BST-2 expression in cancerous epithelial cells but not in cancerous stromal cells. In all panels, numbers correspond to P values. The relative units for BST-2 RNA levels acquired from TCGA and Gene Expression Omnibus (GEO) datasets are SEM-normalized and centralized log2(x + 1). Error bars represent standard deviations and significance was taken at P <0.01**. ns = not significant.
Mentions: Meta-analysis of large-scale human breast cancer data from the GEO and TCGA was used to assess the level of BST-2 mRNA in breast tumors. We compared BST-2 expression in paired normal breast tissues versus resected BRCAs from subjects with known clinical outcomes. BST-2 expression was significantly higher in tumor tissues compared to their paired normal breast tissues (Figure 1A). Stratification of TCGA data into different tumor subtypes showed that compared to normal tissues, BST-2 expression was significantly elevated in all tumor subtypes analyzed with the exception of the basal subtype, where the difference did not reach statistical significance (Figure 1B). Of note, the high-grade luminal B tumors expressed more BST-2 mRNA than the low-grade luminal A, human epidermal growth factor receptor 2 (HER2)+, and basal type (Figure 1B).Figure 1

Bottom Line: In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival.In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival.Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA, 52242-1109, USA. wadiedaniel-mahauadfernandez@uiowa.edu.

ABSTRACT

Introduction: Several innate immunity genes are overexpressed in human cancers and their roles remain controversial. Bone marrow stromal antigen 2 (BST-2) is one such gene whose role in cancer is not clear. BST-2 is a unique innate immunity gene with both antiviral and pro-tumor functions and therefore can serve as a paradigm for understanding the roles of other innate immunity genes in cancers.

Methods: Meta-analysis of tumors from breast cancer patients obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were evaluated for levels of BST-2 expression and for tumor aggressiveness. In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival. In vitro, we assessed the effect of carcinoma cell BST-2 knockdown and/or overexpression on adhesion, anchorage-independent growth, migration, and invasion.

Results: BST-2 in breast tumors and mammary cancer cells is a strong predictor of tumor size, tumor aggressiveness, and host survival. In humans, BST-2 mRNA is elevated in metastatic and invasive breast tumors. In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival. Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

Conclusions: BST-2 contributes to the emergence of neoplasia and malignant progression of breast cancer. Thus, BST-2 may (1) serve as a biomarker for aggressive breast cancers, and (2) be a novel target for breast cancer therapeutics.

Show MeSH
Related in: MedlinePlus