MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer

Abstract

// Xin Xu 1 , Yun Zhang 1 , Jeff Jasper 1 , Erik Lykken 2 , Peter B. Alexander 1 , Geoffrey J. Markowitz 1 , Donald P. McDonnell 1 , Qi-Jing Li 2 , Xiao-Fan Wang 1 1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA 2 Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA Correspondence to: Xiao-Fan Wang, e-mail: xiao.fan.wang@dm.duke.edu Keywords: miR-148a, metastasis, triple-negative breast cancer, extravasation, prognosis biomarker Received: January 03, 2016      Accepted: February 15, 2016      Published: March 07, 2016 ABSTRACT Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models. We have found that miR-148a exhibits properties as a tumor suppressor as its expression is inversely correlated with the ability of both human and mouse breast cancer cells to colonize the lung in mouse xenograft tumor models. Mechanistically, miR-148a appears to suppress the extravasation process of cancer cells, likely by targeting two genes WNT1 and NRP1 in a cell non-autonomous manner. Importantly, lower expression of miR-148a is detected in higher-grade tumor samples and correlated with increased likelihood to develop metastases and poor prognosis in subsets of breast cancer patients, particularly those with TNBC. Thus, miR-148a is functionally defined as a suppressor of breast cancer metastasis and may serve as a prognostic biomarker for this disease.