Tripartite motif-containing 3 (TRIM3) enhances ER signaling and confers tamoxifen resistance in breast cancer

Runyi Ye,Pian Liu,Shenming Wang,Nijiati Aierken,Huijuan Zeng,Ying Lin,Xiaying Kuang,Nan Shao

doi:10.1038/s41389-021-00350-x

Abstract

Tamoxifen resistance remains a clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. Tripartite motif-containing (TRIM) proteins are a new class of SUMO E3 ligases, which regulate the SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and the response to tamoxifen remain unclear. In the present study, we observed that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance. Furthermore, TRIM3 overexpression significantly correlated with poor survival of patients with ER+ breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking down of TRIM3 reduced these capabilities. Moreover, TRIM3, as a ubiquitin carrier protein 9 (UBC9) binding protein, promoted SUMO modification of estrogen receptor 1 (ESR1) and activated the ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance. These results suggest TRIM3 as a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen might provide a potential treatment for breast cancer.

Highlights

Representing almost 25% of cancer cases among women, breast cancer remains a global challenge worldwide [1]
TRIM3 contributes tamoxifen-resistant in breast cancer To determine the molecular mechanism that contributes to breast cancer tamoxifen resistance, we analyzed gene expression in patients with breast cancer from TCGA database
By analyzing published expression profiles obtained from breast cancer (TCGA) data, we found that levels of TRIM3 mRNA correlated positively with levels of the TRIM3 protein, and TRIM3 mRNA expression was upregulated in estrogen receptor (ER)+ breast cancer tissues compared with that in ER− cancer tissues and normal breast tissue (Fig. S1A, B)

Summary

Introduction

Representing almost 25% of cancer cases among women, breast cancer remains a global challenge worldwide [1]. 1234567890();,: Fig. 1 TRIM3 overexpression promotes tamoxifen resistance in breast cancer. 48 ER+ clinical breast cancer specimens after tamoxifen treatment were used to examine the expression of TRIM3 protein (Table S1).

Results

Conclusion