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Abstract
The microRNA-200 (miR-200) family is associated with tumor metastasis and poor patient prognosis. We found that miR-200c/141 cluster overexpression upregulated SerpinB2 in the MDA-MB-231 triple-negative (TN) breast cancer cell line. We observed transcription factor (c-Jun, c-Fos, and FosB) upregulation, nuclear localization of c-Jun, and increased SerpinB2 promoter-directed chloramphenicol acetyltransferase activity in miR-200c/141 cluster-overexpressing cells relative to controls. Additionally, miR-124a and miR-26b, which directly target SepinB2, were downregulated compared to controls. In mouse xenograft models, miR-200c/141 cluster overexpression promoted lymph node and lung metastasis, and siRNA-mediated SerpinB2 knockdown decreased lung metastasis, suggesting that SerpinB2 mediates miR-200c/141-induced lung metastasis. We also explored the clinical significance of SerpinB2 protein status through analysis of primary breast tumor samples and The Cancer Genome Atlas (TCGA) data. High SerpinB2 levels were associated with reduced survival and increased lymph node metastasis in breast cancer patients. SerpinB2 was overexpressed in the TN breast cancer subtype as compared to the luminal subtype. The present study demonstrates that SerpinB2 promotes miR-200c/141 cluster overexpression-induced breast cancer cell metastasis, and SerpinB2 overexpression correlates with increased metastatic potential and unfavorable outcomes in breast cancer patients. SerpinB2 may be a useful biomarker for assessing metastasis risk in breast cancer patients.
Highlights
The microRNA-200 family consists of five members in two clusters, miR-200c/141 and miR200b/a/429, which likely target different, but sometimes overlapping genes, thereby regulating many biological processes as oncomiRs or tumor suppressors [1, 2].Individual miR-200 family member target genes appear to be cancer type- and context-dependent [3]
Our preliminary studies showed that miR-200c/141 cluster overexpression in a triple-negative (TN) human breast cancer cell (BCC) line, MDA-MB-231, which lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal receptor 2 (HER2) expression, enhances the migration and invasion abilities [12], upregulates SerpinB2 and promotes lymph node (LN) and lung metastasis in mouse models
A 47-kDa SerpinB2 was detected in MDA-MB-231miR-200c/141 cell conditioned medium (CM), but large forms (>60-kDa) were highly detected in both control and MDA-MB-231miR-200c/141 cell CM (Figure 1E)
Summary
The microRNA-200 (miR-200) family consists of five members in two clusters, miR-200c/141 and miR200b/a/429, which likely target different, but sometimes overlapping genes, thereby regulating many biological processes as oncomiRs or tumor suppressors [1, 2].Individual miR-200 family member target genes appear to be cancer type- and context-dependent [3]. MiR-200 member expression status serves as a surrogate marker for metastasis, response to drug treatments, and patient outcomes [4,5,6,7,8,9]. Despite advances in our understanding of BC-related miR-200 members, their precise roles in breast cancer cell (BCC) metastasis are largely unknown, in part because each miR-200 has several putative targets with disparate functions. Our preliminary studies showed that miR-200c/141 cluster overexpression in a triple-negative (TN) human BCC line, MDA-MB-231, which lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal receptor 2 (HER2) expression, enhances the migration and invasion abilities [12], upregulates SerpinB2 and promotes lymph node (LN) and lung metastasis in mouse models. The role of SerpinB2 as a prognosis marker in tumor progression or suppression remains controversial
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