NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer

Abstract

Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.

Ubiquitin-Specific Peptidase 8 Modulates Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis in Breast Cancer by Stabilizing Estrogen Receptor Alpha

“…Te signifcant gene sets conformed to the standards of "nominal (NOM) p value <0.05" and "false discovery rate (FDR) q-value <0. 25. "…”

The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets

“…Other molecules have been implicated in endocrine resistance with mechanisms involving ERK activation, including NR4A1 (Nuclear Receptor Subfamily 4 Group A Member 1) [ 117 ], Krüppel-like factor 4 (KLF4) [ 118 ], the nuclear receptor coregulator PELP1 [ 119 ], placenta specific 8 (PLAC8) [ 120 ], fatty acid synthase (FASN) [ 121 ], and the ubiquitin ligase TRIM RING finger protein TRIM2 [ 122 ].…”

Network-informed discovery of multidrug combinations for ERα+/HER2-/PI3Kα-mutant breast cancer

“…In addition, ERα can be activated in an estrogen- independent manner by a large panel of factors, including epidermal growth factor (EGF) (Ignar-Trowbridge et al , 1992; Ignar-Trowbridge et al , 1993), insulin and insulin-like growth factors (IGF) (Newton et al , 1994), PI3K (Campbell et al , 2001), Akt (Campbell et al , 2001; Martin et al , 2000), and hypoxia-inducible factor 1 α (HIF1α) (Cho et al , 2006; Bennesch & Picard, 2015) (see detailed list at https://www.picard.ch/downloads/Factors.pdf). Through various domains, ERα can interact with a plethora of proteins that regulate its activity, such as the MAPKs ERK1/ERK2 (ERK1/2) (Chen et al , 2002; Kato et al , 1995; Kim et al , 2021; Vafeiadou et al , 2022; Li et al , 2012; Mueller et al , 2000; Bunone et al , 1996), mTOR (Alayev et al , 2016), cyclin-dependent kinase inhibitor 1 (p21) (Fritah et al , 2005; Redeuilh et al , 2002; Abukhdeir et al , 2008), and poly (ADP-ribose) polymerase 1 (PARP1) (Schiewer & Knudsen, 2014; Zhang et al , 2013; Pulliam et al , 2019; Gadad et al , 2021) (see the updated list of ERα interactors at https://www.picard.ch/downloads).…”

“…Resistance to tamoxifen can be attributed to multiple mechanisms, including loss of ERα expression or function due to genetic mutations, alterations in the levels of co-regulatory factors (Osborne et al , 2003), upregulation of oncogenic signal transduction pathways, and ligand-independent activation of ERα (Kato et al , 1995; Shim et al , 2000; Coutts & Murphy, 1998; Gee et al , 2001; Clark et al , 2002; Gutierrez et al , 2005; Bennesch & Picard, 2015). For example, ERK1/2 play a critical role in breast cancer and their hyperactivation is associated with tamoxifen resistance and poor prognosis (Gee et al , 2001; Coutts & Murphy, 1998; Shim et al , 2000; Chen et al , 2002; Kato et al , 1995; Kim et al , 2021; Vafeiadou et al , 2022; Li et al , 2012; Mueller et al , 2000; Bunone et al , 1996). ERK1/2 can stimulate cell growth independently of ERα or through signaling crosstalk with ERα.…”

“…The copyright holder for this this version posted September 3, 2022. ; https://doi.org/10.1101/2022.08.30.505871 doi: bioRxiv preprint al, 2002; Gutierrez et al, 2005;Bennesch & Picard, 2015). For example, ERK1/2 play a critical role in breast cancer and their hyperactivation is associated with tamoxifen resistance and poor prognosis (Gee et al, 2001;Coutts & Murphy, 1998;Shim et al, 2000;Chen et al, 2002;Kato et al, 1995;Kim et al, 2021;Vafeiadou et al, 2022;Li et al, 2012;Mueller et al, 2000;Bunone et al, 1996). ERK1/2 can stimulate cell growth independently of ERa or through signaling crosstalk with ERa.…”