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Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer.

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Expression of miR-21, an oncomiR, is frequently altered and may be distinctly expressed in the tumor stroma. Because tumor lesions are a complex mixture of cell types, we hypothesized that analysis of miR-21 expression at single-cell resolution could provide more accurate information to assess disease recurrence risk and BC-related death. We implemented a fully automated, tissue slide-based assay to detect miR-21 expression in 988 patients with BC. The miR-21(High) group exhibited shorter recurrence-free survival [hazard ratio (HR), 1.71; P < 0.001] and BC-specific survival (HR, 1.96; P < 0.001) in multivariate regression analyses. When tumor compartment and levels of miR-21 expression were considered, significant associations with poor clinical outcome were detected exclusively in tumor epithelia from estrogen receptor- and/or progesterone receptor-positive human epidermal growth factor receptor 2-negative cases [recurrence-free survival: HR, 3.67 (P = 0.006); BC-specific survival: HR, 5.13 (P = 0.002)] and in tumor stroma from TNBC cases [recurrence-free survival: HR, 2.59 (P = 0.013); BC-specific survival: HR, 3.37 (P = 0.003)]. These findings suggest that the context of altered miR-21 expression provides clinically relevant information. Importantly, miR-21 expression was predominantly up-regulated and potentially prognostic in the tumor stroma of TNBC.

SUBMITTER: MacKenzie TA

PROVIDER: S-EPMC4258602 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer.

MacKenzie Todd A TA Schwartz Gary N GN Calderone Heather M HM Graveel Carrie R CR Winn Mary E ME Hostetter Galen G Wells Wendy A WA Sempere Lorenzo F LF

The American journal of pathology 20141106 12

Triple-negative breast cancer (TNBC) is an aggressive subtype defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Expression of miR-21, an oncomiR, is frequently altered and may be distinctly expressed in the tumor stroma. Because tumor lesions are a complex mixture of cell types, we hypothesized that analysis of miR-21 expression at single-cell resolution could provide more accurate information to assess disease recurrence ri ...[more]

PMID: 25440114

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Project description:Familial triple-negative breast cancers are often linked to mutations in the BRCA1 tumor suppressor gene. In sporadic triple-negative breast cancers BRCA1 is frequently inactivated at the transcriptional level, and it has been reported that this inactivation may be brought about by promoter methylation. More recently, it was found that BRCA1 may also be regulated at the post-transcriptional level by miRNAs. Here, we explored the expression of putative BRCA1-regulating miRNAs in sporadic human triple-negative breast cancer cells.Nine sporadic human breast cancer-derived cell lines and one benign breast epithelium-derived cell line were assessed for their hormone receptor, growth factor receptor and cytokeratin status by immunocytochemistry. The expression of 5 selected miRNAs predicted to target BRCA1 was assessed using qRT-PCR in the 10 cell lines. In addition, expression profiles of 84 known breast cancer-associated miRNAs were established in these 10 cell lines using PCR Array and qRT-PCR, respectively. The putative role of pre-selected candidate miRNAs in breast cancer development was assessed through exogenous expression of these miRNAs and their anti-miRNAs ('antagomirs') in MDA-MB-231 and MCF7 breast cancer-derived cells.Based on our expression profiling results, four candidate miRNAs (miR-10b, miR-26a, miR-146a and miR-153) were selected as being potentially involved in triple-negative breast cancer development. Exogenous expression assays revealed that miR-10b and miR-26a, but not miR-146a, can down-regulate the expression of BRCA1 in both triple-negative MDA-MB-231 and luminal epithelial MCF7 breast cancer-derived cells, whereas miR-153 could down-regulate BRCA1 expression only in MCF7 cells. In silico analysis of The Cancer Genome Atlas (TCGA) data confirmed that miR-146a is significantly higher expressed in triple-negative breast tumors compared to other (non triple-negative) breast tumors.Our work provides evidence for the involvement of specific miRNAs in triple-negative breast cancer development through regulating BRCA1 expression.

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Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer.

Publications

Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer.

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