Wild-type p53 upregulates an early onset breast cancer-associated gene GAS7 to suppress metastasis via GAS7\u2013CYFIP1-mediated signaling pathway

Jui‐Chi Chang ,Wenling Chen ,Shih-Hsuan Chan,Chen‐Yang Shen ,Shih‐Sheng Jiang ,Fang‐Yu Tsai ,Pei‐Hsin Huang ,King‐Jen Chang ,Shih‐Feng Tsai ,Yih-Huei Uen,Shiao-Lin Tung,I–Shou Chang ,Chi‐Wen Tu ,Kai-Ti Lin,Chiao-Mei Lin,Chung‐Hsing Chen ,Sheng-Chieh Lin,Wen‐Hung Kuo ,Ming‐Feng Hou ,Meng-Fan Chiu,Mingyang Wang ,Lu–Hai Wang

doi:10.1038/s41388-018-0253-9

Abstract

The early onset breast cancer patients (age ≤ 40) often display higher incidence of axillary lymph node metastasis, and poorer five-year survival than the late-onset patients. To identify the genes and molecules associated with poor prognosis of early onset breast cancer, we examined gene expression profiles from paired breast normal/tumor tissues, and coupled with Gene Ontology and public data base analysis. Our data showed that the expression of GAS7b gene was lower in the early onset breast cancer patients as compared to the elder patients. We found that GAS7 was associated with CYFIP1 and WAVE2 complex to suppress breast cancer metastasis via blocking CYFIP1 and Rac1 protein interaction, actin polymerization, and β1-integrin/FAK/Src signaling. We further demonstrated that p53 directly regulated GAS7 gene expression, which was inversely correlated with p53 mutations in breast cancer specimens. Our study uncover a novel regulatory mechanism of p53 in early onset breast cancer progression through GAS7–CYFIP1-mediated signaling pathways.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.In the United States, around 6.6% of breast cancer cases are diagnosed below age of 40 years old [1], whereas in Taiwan, that is about 29.3%
We assessed the role of growth-arrest-specific 7 isoform b (GAS7b) in the highly invasive MDA-MB-231-IV2 subline by orthotopic implantation in mouse model, and the results demonstrated that MDA-MB-231-IV2 cells overexpressing GAS7b had reduced lymph-node metastasis (Fig. 5d), but there was no inhibition of tumor growth at the primary site (Fig. 5e and Supplementary Figure S11)
For younger age group of breast cancer patients, there is a higher frequency of grade 3 tumors, higher lymphatic invasion, lower estrogen receptor (ER) and progesterone receptor (PR) positivity, higher human epidermal growth factor receptor 2 (HER-2) expression, and larger tumors [1, 26, 27]

Summary

Introduction

Chia-Yi Christian Hospital, Chiayi, Taiwan 12 Department of Surgery, College of Medicine, Kaohsiung Medical. Previous studies have demonstrated that GAS7 can promote neurite-like outgrowth of cells, and it co-localizes with microfilaments in membrane ruffles concurrent with actin assembly and membrane outgrowth [8, 9]. We demonstrated that GAS7b interacted with CYFIP1 protein, and disrupted interaction between CYFIP1 and active form of Rac, leading to blocking of actin polymerization, and reduced β1-integrin/ FAK/Src signaling. This resulted in the suppression of breast cancer cell migration/invasion and metastasis. Wild-type p53 upregulates an early onset breast cancer-associated gene GAS7 to suppress metastasis via. Our study identified GAS7b to be related to poor prognosis of early onset breast cancer and can serve as a potential prognostic biomarker for breast cancer metastasis

Result

Discussion

Materials and methods

Findings

Compliance with ethical standards