DACH1 suppresses breast cancer as a negative regulator of CD44

Hanxiao Xu,Dong Kuang,Richard G Pestell,Xun Yuan,Shengnan Yu,Jing Xiong,Kongming Wu

doi:10.1038/s41598-017-04709-2

Abstract

Dachshund homolog 1 (DACH1), a key cell fate determination factor, contributes to tumorigenesis, invasion, metastasis of human breast neoplasm. However, the exact molecular mechanisms for the anti-tumor roles of DACH1 in breast carcinoma are still lack of extensive understanding. Herein, we utilized immunohistochemistry (IHC) staining and public microarray data analysis showing that DACH1 was higher in normal breast, low-grade and luminal-type cancer in comparison with breast carcinoma, high-grade and basal-like tumors respectively. Additionally, both correlation analysis of public databases of human breast carcinoma and IHC analysis of mice xenograft tumors demonstrated that DACH1 inversely related to cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) inducers and basal-enriched molecules, while cluster of differentiation 44 (CD44) behaved in an opposite manner. Furthermore, mice transplanted tumor model indicated that breast cancer cells Met-1 with up-regulation of DACH1 were endowed with remarkably reduced potential of tumorigenesis. Importantly, meta-analysis of 19 Gene Expression Omnibus (GEO) databases of breast cancer implicated that patients with higher DACH1 expression had prolonged time to death, recurrence and metastasis, while CD44 was a promising biomarker predicting worse overall survival (OS) and metastasis-free survival (MFS). Collectively, our study indicated that CD44 might be a novel target of DACH1 in breast carcinoma.

Highlights

In spite of significant achievement made in early diagnosis and therapeutic strategies, breast cancer still draws great attention from the worldwide because of its high incidence rate and mortality[1,2,3]
In order to evaluate the expression of Dachshund homolog 1 (DACH1) and Cluster of differentiation-44 (CD44) in normal breast and breast malignant tissues, we carried out IHC analysis on two tissue microarray (TMA) (BR1502–97 and BR1502-98) with normal breast and human breast cancer tissues
DACH1 was majorly found in nucleus and CD44 was mostly detected on the membrane of breast cancer cells

Summary

Introduction

In spite of significant achievement made in early diagnosis and therapeutic strategies, breast cancer still draws great attention from the worldwide because of its high incidence rate and mortality[1,2,3]. SIX1 and EYA1, two important RDGN members, exert favorable effects on tumor initiation and progression[4, 5], and high expression of SIX1 and EYA1 is an adverse factor for clinical outcomes for breast cancer patients[6,7,8]. As a well-known marker of CSCs, CD44 promotes carcinogenesis, invasion, metastasis and therapy-resistance[20,21,22,23]. It promotes proliferation and suppresses apoptosis by regulation of relative pathways, including Ras-Raf-Mek-Erk-Cyclin D1. Our study indicated that DACH1 was inversely correlated with CD44 and CD44 might be a novel target of DACH1 in breast cancer

Methods

Results

Conclusion