TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression

Abstract

Background Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. Methods TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT–PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT–PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. Results In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. Conclusion Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Graphical abstract

Identification of breast cancer subgroups and immune characterization based on glutamine metabolism-related genes

“…Estrogen mainly promotes BC cell growth by activating estrogen receptors, and estrogen is pivotal in progression from primary BC to metastatic BC [ 54 ]. Zhuang et al [ 55 ] found that TRIM3 promotes BC cell migration and proliferation by promoting estrogen signaling. We speculated that channel activity biological function and Estrogen signaling pathway may be critical in BC prognosis.…”

In Silico Identification of Genes Associated with Breast Cancer Progression and Prognosis and Novel Therapeutic Targets

“…High SPDEF expression was reported to be more common in the luminal type and is positively correlated with the TNM stage, lymphoid nodal status, and tumor invasion, with a poor prognosis in high-expression groups [ 30 , 31 , 32 ]. TRIM3 promotes estrogen signaling and BC progression [ 33 ]. The results of these previous studies are consistent with those of the present study.…”