Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer.
10.1097/CM9.0000000000002930
- Author:
Feng XU
1
;
Kun XU
2
;
Lingling FAN
1
;
Xintong LI
1
;
Yiqiu LIU
1
;
Fang YANG
3
;
Chengjun ZHU
1
;
Xiaoxiang GUAN
1
Author Information
1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
2. Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, China.
3. The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China.
- Publication Type:Journal Article
- MeSH:
Humans;
Androgens/therapeutic use*;
Estrogen Receptor beta/metabolism*;
Receptors, Androgen/therapeutic use*;
Triple Negative Breast Neoplasms/metabolism*;
Molecular Docking Simulation;
Cell Line, Tumor
- From:
Chinese Medical Journal
2024;137(3):338-349
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism.
METHODS:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR.
RESULTS:Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter -42 bp to -28 bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial-mesenchymal transition in tumor progression.
CONCLUSIONS:This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.
