Identification of the Novel Tumor Suppressor Role of FOCAD/miR-491-5p to Inhibit Cancer Stemness, Drug Resistance and Metastasis via Regulating RABIF/MMP Signaling in Triple Negative Breast Cancer.

Wei-Chieh Huang,Yi-Ching Huang,Po-Ming Chen,Hsiang-Cheng Chi,Shiao-Lin Tung,Ya-Chi Shih,Pei-Yi Chu

doi:10.3390/cells10102524

Abstract

Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to development of chemoresistance and lack of effective endocrine or targeted therapies. MiR-491-5p has been found to play a tumor suppressor role in many cancers including breast cancer. However, the precise role of miR-491-5p in TNBC has never been elucidated. In this study, we reported the novel tumor suppressor function of FOCAD/miR-491-5p in TNBC. High expression of miR-491-5p was found to be associated with better overall survival in breast cancer patients. We found that miR-491-5p could be an intronic microRNA processed form FOCAD gene. We are the first to demonstrate that both miR-491-5p and FOCAD function as tumor suppressors to inhibit cancer stemness, epithelial-mesenchymal transition, drug resistance, cell migration/invasion, and pulmonary metastasis etc. in TNBC. MiR-491-5p was first reported to directly target Rab interacting factor (RABIF) to downregulate RABIF-mediated TNBC cancer stemness, drug resistance, cell invasion, and pulmonary metastasis via matrix metalloproteinase (MMP) signaling. High expression of RABIF was found to be correlated with poor clinical outcomes of breast cancer and TNBC patients. Our data indicated that miR-491-5p and RABIF are potential prognostic biomarkers and targeting the novel FOCAD/miR-491-5p/RABIF/MMP signaling pathway could serve as a promising strategy in TNBC treatment.

Highlights

Among female patients, breast cancer remains the most commonly occurring cancer and causes the second highest number of cancer deaths [1]
We further examined the functional role of miR-491-5p in regulating cancer stemness in vitro since triple-negative breast cancer (TNBC) reportedly demonstrates highly chemoresistant behavior and cancer stem cells (CSCs) play important roles in cancer initiation, metastasis, recurrence, and chemoresistance [6,32,33]
We unveiled the novel tumor suppressor role of FOCAD/miR-491-5p via targeting Rab interacting factor (RABIF)/matrix metalloproteinase (MMP) signaling in TNBC for the first time

Summary

Introduction

Breast cancer remains the most commonly occurring cancer and causes the second highest number of cancer deaths [1]. TNBC, the most aggressive type of breast cancer, is characterized by the absence of estrogen receptors (ER) and progesterone receptors (PR) and the amplification of human epidermal growth factor receptor 2 (HER2) [2,3,4]. Chemoresistance to initial chemotherapy, frequent recurrence, and lack of effective endocrine or targeted therapies lead to a poor prognosis for TNBC [3,5,6]. While a few targeted therapies, including inhibitors of the mammalian target of rapamycin (mTOR), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF), have been recently applied in TNBC treatment, the effects remain unsatisfactory. There is, an urgent need to explore new therapeutic targets [6]

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Conclusion