GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis

Abstract

Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Our previous studies find that GPER and its down-stream signaling play a pivotal role in the development of tamoxifen (TAM) resistance. cDNA array analysis indicated a set of genes associated with cell apoptosis are aberrant in GPER activated and TAM-resistant MCF-7R cells compared with TAM-sensitive MCF-7 cells. Among these genes, Bim (also named BCL2-L11), a member of the BH3-only pro-apoptotic protein family is significantly decreased, and TRIM RING finger protein TRIM2 (a ubiquitin ligase) is highly expressed in MCF-7R. To understand the mechanism of TAM-resistance in GPER activated ER+ breast cancer, the function of TRIM2 and Bim inducing cell apoptosis was studied. By using immunohistochemical and western blot analysis, there is an adverse correlation between TRIM2 and Bim in TAM-resistant breast tumor tissues and MCF-7R cells. Knockdown Bim in TAM-sensitive MCF-7 cells or overexpression of Bim in TAM-resistant MCF-7 cells significantly changed its sensibility to TAM through altering the levels of cleaved PARP and caspase-3. Activation of GPER and its downstream signaling MAPK/ERK, not PI3K/AKT, led to enhanced TRIM2 protein levels and affected the binding between TRIM2 and Bim which resulted in a reduced Bim in TAM-resistant breast cancer cells. Thus, the present study provides a novel insight to TAM-resistance in ER-positive breast cancer cells.

TRIM2 downregulation in clear cell renal cell carcinoma affects cell proliferation, migration, and invasion and predicts poor patients’ survival

“…Normal function of von Hippel–Lindau tumor suppressor, which could deregulate hypoxia-inducible transcription factor (HIF) loss, was one of the most pathogens in ccRCC, and HIF-2a acting as an important oncogene could promote renal tumor growth. 29 – 32 Previous studies indicated that TRIM2 functions as a direct regulator to Bim degradation in TAM-resistant breast cancer cells and ovarian cancer, 26 , 27 and GSEA demonstrated that low TRIM2 expression was associated with the hypoxia signaling pathways in patients with ccRCC; it may be hypothesized that TRIM2 could negatively regulated hypoxia signaling pathways, or even deregulated HIF expression in ccRCC; further experiments need to be verified this.…”

“… 25 However, some certain studies showed the opposite results with the expression of TRIM2 found to be upregulated in ovarian and breast cancers. 26 , 27 The bias between different types of cancer suggests that TRIM2 is an important gene involved in the pathogenic process of cancer by different mechanisms and microenvironments. The dysfunction of TRIM2 may be one of the factors involved in the occurrence and development of ccRCC to a certain extent, and the association between TRIM2 and renal cancer has not been reported.…”

Zinc finger protein 32 promotes breast cancer stem cell-like properties through directly promoting GPER transcription

“…GPER has also been reported to contribute to pathological responses, such as cancer cell proliferation, migration and invasion, especially during breast cancer development 11 , 13 . Approximately 50% of breast cancer patients have been reported to express GPER, which is consistent with the development of tamoxifen resistance 14 , 15 . In vivo study from transgenic mouse tumour models showed that deletion of GPER reduced the size of mammary tumours and lung metastasis, indicating that GPER is critical for breast tumour growth and distant metastasis 16 .…”

Context-Specific Coordinately Regulatory Network Prioritize Breast Cancer Genetic Risk Factors

“…The top-ranked PCG VEGFA, involved with miR-205 and FGF2, contributed to the resistance to chemotherapeutics in BC, which promoted the BC progression and suppressed cell apoptosis (Hu et al, 2016). Another top-ranked PCG BCL2L11 was involved in tamoxifen response of BC by disturbing the expression levels of cleaved PARP and caspase-3, which would affect BC prognosis (Yin et al, 2017). The extensive literature survey exhibited the feasibility of our method to predict BCassociated risk factors.…”