SRGN-TGF\u03b22 regulatory loop confers invasion and metastasis in triple-negative breast cancer

Z Zhang,M Lu,Ni Qiu,G Zheng,Y Deng,H Liu,Q Qiu,Y Gu,X Jia,Y Xiong,K Luo,Z He,J Yin

doi:10.1038/oncsis.2017.53

Abstract

Patients with triple-negative breast cancers (TNBC) are at a high risk for a recurrent or metastatic disease, and the molecular mechanisms associated with this risk are unclear. Proteoglycan serglycin (SRGN) proteins are involved in tumor metastasis, but their role in TNBC has not yet been elucidated. This study investigates the SRGN gene expression and how it regulates TGFβ2 and the downstream signaling of TGFβ2 in TNBC cells and tissues. Our results show that SRGN mRNA and protein expression levels were significantly higher in TNBC cell lines and tumor tissues than that in non-TNBC cells and tissues. We inhibited SRGN expression and protein secretion using shRNA and we observed this inhibited the invasive motility of TNBC cancer cells in vitro and metastasis of TNBC cancer cells in vivo. SRGN protein treatment increased the expression and secretion of transforming growth factor-β2 (TGFβ2) by activating CD44/CREB1 signaling and promoted epithelial-to-mesenchymal transition in TNBC cells. Moreover, TGFβ2 treatment increased the mRNA and protein expression of the SRGN gene by activating Smad3 to target the SRGN relative promoter domain in TNBC cells. Our findings demonstrate that SRGN interacts with TGFβ2 which regulates TNBC metastasis via the autocrine and paracrine routes. SRGN could serve as a potential target for development of agents or therapeutics for the TNBC.

Highlights

Breast cancer is one of the most common malignancies for women
SRGN mRNA (Figure 1a) and protein (Figure 1b) expression levels were significantly higher in the triple-negative breast cancers (TNBC) cells (MDA-MB-231 and BT549 cell), than other subtypes of BC cells
We further measured mRNA expression of the SRGN gene using RT–PCR in tissues from 106 cases of TNBC and 320 cases of other BC types and we found that TNBC tumors contained significantly higher SRGN mRNA levels compared with other BC types (P o0.001, Figure 1d)

Summary

Introduction

Breast cancer is one of the most common malignancies for women. the treatment of breast cancer has greatly improved over the past few decades, there are still around 50 million people worldwide that die from breast cancer every year. SRGN mRNA and protein expression increases in breast cancer cells and tissues

Results

Conclusion