UBE2M forms a positive feedback loop with estrogen receptor to drive breast cancer progression and drug resistance

Sep 21, 2026

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Breast cancer remains highly lethal, especially ERα-positive disease that relies on estrogen receptor signaling and is treated with fulvestrant yet frequently accompanied by relapse and acquired drug resistance. The study investigates how neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) neddylation, particularly via the E2 enzyme UBE2M, regulates oncogenic pathways by activating Cullin-RING E3 ligases (CRLs). It links overactivated neddylation to enhanced degradation of tumor suppressors, cancer progression, and potential resistance mechanisms, supporting UBE2M/neddylation as a therapeutic target to improve fulvestrant sensitivity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Estrogen receptor signaling and fulvestrant resistance

Neddylation pathway and CRL activation

UBE2M function in cancer and treatment sensitivity

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN UBE2M forms a positive feedback loop with estrogen receptor to drive breast cancer progression and drug resistance Xiongzhi Lin1,2,4, Dongsheng Sun1,4, Shuhan Yang 1, Kai Cheng1, XingYi Wang1, Weijia Meng1, Haowei Wu1, Wenlin Liu1, Xiaoyu Wu1, Hui Yang 3, Xiaojun Wang 1 ✉ and Lisha Zhou 1 ✉ © The Author(s) 2024 INTRODUCTION Breast cancer has the highest incidence and mortality rates of all cancer types among women worldwide [1] . Estrogen receptorpositive (ER+) breast cancer is the most common subtype and accounts for >70% of all breast cancer cases [2] . ERα, an estrogendependent nuclear transcription factor, plays a crucial role in the progression of breast cancer by driving the transcription of prosurvival genes and activating cellular signalling. Therefore, estrogen inhibitors and ER antagonists may serve as effective drugs for endocrine therapy in ER+ breast cancer [3] . Fulvestrant is a selective estrogen receptor downregulator (SERD) that targets ERα for proteasome-dependent degradation. Among several drugs used in endocrine therapy, fulvestrant is considered asthe ﬁrst-line drug for treating advanced or metastatic ER+ breast cancer in postmenopausal women [4, 5] . However, the overall survival (OS), relapse-free survival (RFS) and progression-free survival (PFS) rates remain low despite fulvestrant treatment (Clinical [trials.gov](trials.gov), Number: NCT02422615; NCT00629616; NCT02690480), and drug resistance develops over time [6–8] . Understanding the molecular mechanisms underlying the occurrence and development of breast cancer and identifying novel therapeutic targets may help to develop strategies for improving fulvestrant sensitivity in ER+ breast cancer. Neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) is a ubiquitin-like protein associated with a post-translational modiﬁcation, known as neddylation [9] . Similar to ubiquitination, neddylation is a process that conjugates NEDD8 to substrate proteins through three successive enzymatic cascades: NEDD8-activating enzyme E1 (NAE, a heterodimer of NAE1 and UBA3), NEDD8-conjugating enzyme E2 (UBE2M or UBE2F) and substrate-speciﬁc NEDD8-E3 ligases [10–12] . Neddylation and ubiquitination are two distinct processes, each involving its own set of E1 and E2 enzymes. The E3 enzymes involved in both processes are occasionally shared [13] . NEDD8 was initially discovered to be involved in the development of neural precursor cells [14] . Subsequent extensive studies have demonstrated that NEDD8 and enzymes of neddylation pathway are frequently overexpressed in various human cancers, including breast cancer. This overexpression is associated with disease progression and predicts poor patient survival [15–18] . The primary physiological substrates of neddylation are members of the Cullin family, such as CUL 1, 2, 3, 4 A, 4B and 5 [19] . Each Cullin protein serves as a scaffold subunit of Cullin-RING E3 ligases (CRLs), which constitute the largest family of multiunit E3 ubiquitin ligases. They control the degradation of approximately 20% of proteasome-regulated proteins and are involved in many important biological processes [20, 21] . Activation of CRLs requires the conjugation of NEDD8 to a key lysine residue at the C-terminus of Cullins. This induces aconformational change that dissociates the negative regulator CAND1 from CRLs and facilitates the assembly of functional CRLs for subsequent substrate ubiquitination [22–26] . Given that overactivation of CRLs leads to cancer growth and development, targeting the neddylation of Cullins appears to be an attractive approach for cancer treatment [27, 28] . Overactivation of neddylation pathway leads to increased neddylation modiﬁcation levels of Cullins, promoting the subsequent degradation of tumor 1Taizhou Central Hospital (Taizhou University Hospital), School of Medicine, Taizhou University, Taizhou, Zhejiang, China. 2

FAQs

Why is estrogen receptor signaling central in ER+ breast cancer?

ERα is an estrogen-dependent nuclear transcription factor that drives transcription of prosurvival genes and activates cellular signaling, making endocrine therapies effective but also prone to resistance over time.

What is neddylation and how does it relate to cancer progression?

Neddylation conjugates NEDD8 to substrate proteins through E1, E2, and E3 cascades. Overactivation of this pathway enhances Cullin modification, promotes tumor suppressor degradation, and supports carcinogenesis and progression.

How does UBE2M influence tumor growth and treatment response?

UBE2M is strongly correlated with global protein neddylation and supports activation of the neddylation pathway. Its downregulation suppresses proliferation and can enhance sensitivity to DNA damage, suggesting a role in therapeutic effectiveness and resistance.

Sep 21, 2026

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