DLG5 suppresses breast cancer stem cell-like characteristics to restore tamoxifen sensitivity by inhibiting TAZ expression

Jie Liu; Juan Li; Pingping Li; Yina Jiang; He Chen; Ruiqi Wang; Fang Cao; Peijun Liu

doi:10.1111/jcmm.13954

DLG5 suppresses breast cancer stem cell-like characteristics to restore tamoxifen sensitivity by inhibiting TAZ expression

J Cell Mol Med. 2019 Jan;23(1):512-521. doi: 10.1111/jcmm.13954. Epub 2018 Nov 18.

Authors

Jie Liu^{1

2}, Juan Li^{1

2}, Pingping Li^{1

2}, Yina Jiang³, He Chen^{1

2}, Ruiqi Wang^{1

2}, Fang Cao^{1

2}, Peijun Liu^{1

2}

Affiliations

¹ Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
² Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
³ Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Abstract

Tamoxifen (TAM) is a primary drug for treatment of estrogen receptor positive breast cancer. However, TAM resistance remains a serious threat to breast cancer patients and may be attributed to increased stemness of breast cancer. Here, we show that discs large homolog 5 (DLG5) expression is down-regulated in TAM-resistant breast cancer and cells. DLG5 silencing decreased the sensitivity to TAM and increased the frequency and stemness of CD44⁺ /CD24^- breast cancer stem cells (BCSCs) and TAZ, a transducer of the Hippo pathway, expression in MCF7 cells while DLG5 overexpression had opposite effects. TAZ silencing restored the sensitivity to TAM and reduced the frequency and stemness in TAM-resistant breast cancer cells. Taken together, our data indicate that down-regulated DLG5 expression increases the stemness of breast cancer cells by enhancing TAZ expression, contributing to TAM resistance in breast cancer.

Keywords: DLG5; TAZ; stemness; tamoxifen resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Hormonal / pharmacology
Breast / drug effects
Breast / metabolism
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism*
Cell Line, Tumor
Down-Regulation / drug effects
Down-Regulation / physiology
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / physiology
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / physiology
Gene Silencing / drug effects
Gene Silencing / physiology
Humans
MCF-7 Cells
Membrane Proteins / metabolism*
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Protein Serine-Threonine Kinases / metabolism
Receptors, Estrogen / metabolism
Tamoxifen / pharmacology*
Trans-Activators / metabolism*
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Tumor Suppressor Proteins / metabolism*

Substances

Antineoplastic Agents, Hormonal
DLG5 protein, human
Membrane Proteins
Receptors, Estrogen
Trans-Activators
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Tumor Suppressor Proteins
WWTR1 protein, human
Tamoxifen
Protein Serine-Threonine Kinases