MicroRNA-200c and microRNA- 141 are regulated by a FOXP3-KAT2B axis and associated with tumor metastasis in breast cancer

Guangxin Zhang,Erica Stringer-Reasor,Runhua Liu,Bingjin Li,Shi Wei,Ranji Cui,Sejong Bae,Wei-Hsiung Yang,Liyan Sun,Lizhong Wang,Dongquan Chen,Chengjing Chu,Kenneth Jiao,Wei Zhang

doi:10.1186/s13058-017-0858-x

Abstract

BackgroundMembers of the microRNA (miR)-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive.MethodsWe investigated FOXP3-inducible breast cancer cells, Foxp3 heterozygous Scurfy mutant (Foxp3sf/+) female mice, and patients with breast cancer for characterization of the formation and regulation of the miR-200 family in breast cancer cells and circulation. Participants (259), including patients with breast cancer or benign breast tumors, members of breast cancer families, and healthy controls, were assessed for tumor and circulating levels of the miR-200 family.ResultsFirst, we identified a FOXP3-KAT2B-miR-200c/141 axis in breast cancer cells. Second, aging Foxp3sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and miR-141 were lower in Foxp3sf/+ tumor cells than in normal breast epithelial cells, but plasma levels of miR-200c and miR-141 in the Foxp3sf/+ mice increased during tumor progression and metastasis. Third, in patients with breast cancer, the levels of miR-200c and 141 were lower in FOXP3low relative to those with FOXP3high breast cancer cells, especially in late-stage and metastatic cancer cells. The levels of miR-200c and miR-141 were higher in plasma from patients with metastatic breast cancer than in plasma from those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or from healthy controls. Finally, in Foxp3sf/+ mice, plasma miR-200c and miR-141 appeared to be released from tumor cells.ConclusionsmiR-200c and miR-141 are regulated by a FOXP3-KAT2B axis in breast cancer cells, and circulating levels of miR-200c and miR-141 are potential biomarkers for early detection of breast cancer metastases.

Highlights

Members of the microRNA-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive
High levels of circulating miR-200 s in breast cancer patients are associated with increased numbers of circulating tumor cells (CTCs) [21], which are a predictor of metastasis up to 2 years prior to clinical diagnosis [22] and of shorter brainmetastasis-free survival [23]
Since endogenous FOXP3 is expressed in the normal immortalized human epithelial cell line, MCF10A [31], we knocked down FOXP3 in MCF10A cells by short hairpin RNAs [31] and found that expressions of miR-200c and miR-141 in the cells were decreased after FOXP3 silencing (Additional file 1: Figure S1A-B)

Summary

Introduction

Members of the microRNA (miR)-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive. MiRs are remarkably stable in the circulation, and in formalin-fixed, paraffin-embedded tissues [4] They have potential to serve as breast cancer biomarkers. Some studies suggest that, in cancer cells, miR-200 s promote tumor metastasis through promotion of tumor colonization at metastatic sites [13, 14]. High levels of circulating miR-200 s in breast cancer patients are associated with increased numbers of circulating tumor cells (CTCs) [21], which are a predictor of metastasis up to 2 years prior to clinical diagnosis [22] and of shorter brainmetastasis-free survival [23]. The cellular origin, mechanism of release, and function of circulating miR-200 s during tumor progression and metastasis remain elusive

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Discussion

Conclusion