Regulation of miRNA-29c and its downstream pathways in preneoplastic progression of triple-negative breast cancer.

Anjana Bhardwaj,Nivetha Ganesan,Cristian Coarfa,Kazunoshin Tachibana,Preethi H Gunaratne,Kimal Rajapakshe,Yinghong Pan,Harpreet Singh,Isabelle Bedrosian

doi:10.18632/oncotarget.14902

Abstract

Little is understood about the early molecular drivers of triple-negative breast cancer (TNBC), making the identification of women at risk and development of targeted therapy for prevention significant challenges. By sequencing a TNBC cell line-based breast cancer progression model we have found that miRNA-29c is progressively lost during TNBC tumorigenesis. In support of the tumor suppressive role of miRNA 29c, we found that low levels predict poor overall patient survival and, conversely, that ectopic expression of miRNA-29c in preneoplastic cell models inhibits growth. miRNA-29c exerts its growth inhibitory effects through direct binding and regulation of TGFB-induced factor homeobox 2 (TGIF2), CAMP-responsive element binding protein 5 (CREB5), and V-Akt murine thymoma viral oncogene homolog 3 (AKT3). miRNA-29c regulation of these gene targets seems to be functionally relevant, as TGIF2, CREB5, and AKT3 were able to rescue the inhibition of cell proliferation and colony formation caused by ectopic expression of miRNA-29c in preneoplastic cells. AKT3 is an oncogene of known relevance in breast cancer, and as a proof of principle we show that inhibition of phosphoinositide 3-kinase (PI3K) activity, a protein upstream of AKT3, suppressed proliferation in TNBC preneoplastic cells. We explored additional opportunities for prevention of TNBC by studying the regulation of miRNA-29c and identified DNA methylation to have a role in the inhibition of miRNA-29c during TNBC tumorigenesis. Consistent with these observations, we found 5 aza-cytadine to relieve the suppression of miRNA-29c. Together, these results demonstrate that miRNA-29c loss plays a key role in the early development of TNBC.

Highlights

Breast cancer is the most common cancer in women worldwide [1]
In support of the tumor suppressive role of miRNA 29c, we found that low levels predict poor overall patient survival and, that ectopic expression of miRNA-29c in preneoplastic cell models inhibits growth. miRNA29c exerts its growth inhibitory effects through direct binding and regulation of TGFBinduced factor homeobox 2 (TGIF2), CAMP-responsive element binding protein 5 (CREB5), and V-Akt murine thymoma viral oncogene homolog 3 (AKT3). miRNA29c regulation of these gene targets seems to be functionally relevant, as TGIF2, CREB5, and AKT3 were able to rescue the inhibition of cell proliferation and colony formation caused by ectopic expression of miRNA-29c in preneoplastic cells
We demonstrated that miRNA-29c plays a tumor suppressor role in the preneoplastic phase of tumorigenesis and showed that miRNA-29c inhibition of cell proliferation and colony formation is at least in part mediated by its gene targets V-Akt murine thymoma viral oncogene homolog 3 (AKT3), TGFB-induced factor homeobox 2 (TGIF2), and CAMP-responsive element binding protein 5 (CREB5)

Summary

Introduction

Breast cancer is the most common cancer in women worldwide [1]. Despite the many advances in the field of breast cancer treatment, challenges still prevail in management of breast cancer patients leading to over 40,000 breast cancer-related deaths every year in the United States alone [2]. MiRNA29c regulation of these gene targets seems to be functionally relevant, as TGIF2, CREB5, and AKT3 were able to rescue the inhibition of cell proliferation and colony formation caused by ectopic expression of miRNA-29c in preneoplastic cells.

Results

Conclusion