Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways.

Wenzhong Zhou,Yongjiu Wang,Qiang Zhang,Liang Li,Fei Zhou,Zhongbing Ma,Gengshen Yin,Chunmiao Ye,Yujuan Xiang,Qinye Fu,Dezong Gao,Liyuan Liu,Fei Wang,Lixiang Yu,Shuya Huang,Zhigang Yu

doi:10.21147/j.issn.1000-9604.2020.03.06

Abstract

ObjectiveObesity is closely associated with metastasis in breast cancer patients. Secreted frizzled-related protein 5 (SFRP5), one of the novel adipokines with anti-inflammatory properties, is associated with obesity. This study aims to study the role of SFRP5 in the crosstalk between obesity and breast cancer metastasis and identify the underlying mechanism.Methods3T3-L1 pre-adipocytes were differentiated to mature adipocytes and a hypertrophic adipocyte model was induced with palmitic acid (PA). Cell motility was measured in MDA-MB-231 and MCF-7 breast cancer cells co-cultured with adipocytes conditioned medium (CM) with or without SFRP5 protein. Wnt and epithelial-mesenchymal transition (EMT) signal pathways were investigated by western blot. Circulating SFRP5 level in 218 breast cancer patients and the association with clinicopathologic characteristics of breast cancer were further determined. Online databases ENCORI and PREDICT Plus were used to exam the link between SFRP5 and prognosis.ResultsReduced SFRP5 level was detected in the hypertrophic adipocyte model. Recombinant SFRP5 protein inhibited MDA-MB-231 and MCF-7 cells invasion and migration induced by PA-treated adipocyte CM, and SFRP5 inhibition by specific antibody reversed the effect of SFRP5. Furthermore, SFRP5 significantly inhibited Wnt and downstream EMT in breast cancer cells. Low circulating SFRP5 level correlated with body mass index (BMI), lymph node (LN) metastasis, TNM stage and high Ki67 expression in breast cancer patients. Increased SFRP5 level was associated with favorable predicted survival. Kaplan-Meier curves showed high SFRP5 level in tumor tissue was associated with better outcome of breast cancer patients.ConclusionsOur findings demonstrated SFRP5 is a vital adipokine that mediates the crosslink between obesity and the metastatic potential of breast cancer. Promotion of SFRP5 expression in the adipose microenvironment may represent a novel approach for preventing breast cancer metastasis.

Highlights

A growing body of epidemiological and clinical evidence supports a strong relationship between obesity and breast cancer risk, metastasis and outcome [1,2]
The results showed that, Secreted frizzled-related protein 5 (SFRP5) level was significantly reduced in the supernatant of adipocytes treated with palmitic acid (PA) compared with control group (2.37±1.14 ng/mL vs. 5.68±1.85 ng/mL, P
Our results showed that lower SFRP5 level was detected in breast cancer patients with lymph node (LN) metastasis, higher Ki67 expression and TNM stage (Table 1), all of which indicated for poorer prognosis

Summary

Introduction

A growing body of epidemiological and clinical evidence supports a strong relationship between obesity and breast cancer risk, metastasis and outcome [1,2]. Obesity promotes breast cancer progression by altering tumor microenvironment to facilitate metastatic dissemination or metabolic reprogramming. Adipocytes represents the most abundant cell type of the breast cancer microenvironment [3,4,5]. Previous studies have shown that adipocytes can act as an endocrine organ, secreting signaling molecules, such as metabolic substrates, adipokines and cytokines. Adipokines such as leptin and adiponectin have been shown to exert critical roles in breast cancer cell behaviors. Except for adiponectin, few of these adipokines play a positive role in regulating obesity-related breast cancer progression

Methods

Results

Discussion

Conclusion