Key Takeaways & Executive Findings
- •• HECTD3 is overexpressed in a majority of breast cancer cases (73-75%) compared to normal tissue (41%). • Positive HECTD3 expression correlates with lower lymph node metastasis, better tumor differentiation, and smaller tumor size. • HECTD3 may serve as a prognostic biomarker indicating good prognosis in breast cancer. • The study provides evidence that HECTD3 could be a potential therapeutic target or diagnostic marker.
Abstract
HECTD3 is an E3 ubiquitin ligase that has been implicated in cancer progression. This study investigates HECTD3 expression in breast cancer and its association with prognosis. Immunohistochemical staining was performed on 320 breast cancer samples (cohort 1) and a tissue microarray of 227 samples (cohort 2), along with 39 normal adjacent tissues. HECTD3 was overexpressed in 73.75% of cohort 1 and 75.33% of cohort 2, compared to 41.03% in normal tissues (P < 0.0001). Logistic regression analysis revealed that positive HECTD3 expression was significantly associated with lower risk of lymph node metastasis (OR = 0.37, P = 0.003), reduced risk of poor tumor differentiation (grade 3 vs 1-2, OR = 0.09, P < 0.0001), and smaller tumor size (≤2 cm vs >2 cm, OR = 0.16, P < 0.0001). These associations persisted after age adjustment. The findings suggest that HECTD3 overexpression is a favorable prognostic marker in breast cancer.
1. Introduction
Ubiquitination is a posttranslational protein modification. Dysfunction of ubiquitination may result in many diseases, including breast cancer [1,2]. Ubiquitin (Ub) chains are assembled by a cascade of reactions catalyzed by Ub-activating enzymes (E1), Ub-conjugating enzymes (E2), and Ub-protein ligases (E3). E3 ligases are responsible for substrate specificity. Several E3 ligases are believed to act as oncoproteins or tumor suppressors because of the genetic and expression alterations they undergo in cancer [3,4].
HECTD3 (homologous to the E6-associated protein carboxyl terminus domain containing 3) E3 ligase contains a conserved HECT domain at the C-terminus. It has already been reported that HECTD3, which is truncated at the N-terminus, recognizes and binds to trio-associated repeats on actin (Tara) for Ub-mediated degradation [5]. Our previous studies revealed that HECTD3 confers resistance to apoptosis in cancer cells by ubiquitinating MALT1 and Caspase-8 [6,7]. Previously, HECTD3 was shown to ubiquitinate Caspase-9 [8]. HECTD3 is upregulated in esophageal squamous cell carcinoma, breast cancer, prostate cancer, and ovarian cancer [6–9]. Previously, we reported that the HECTD3 protein is overexpressed in 42/79 (53%) breast carcinomas [7]. The positive rate was 6/42 (14%) for normal breast tissue samples or normal breast tissues adjacent to invasive carcinomas [7]. A previous study revealed that high HECTD3 expression levels were detected in 46.7% of 150 ovarian cancer samples via a tissue microarray [9]. This proportion is significantly associated with poor platinum response and prognosis in ovarian cancer patients [9]. These data suggest that HECTD3 overexpression may underlie both intrinsic and acquired resistance to platinum-based chemotherapy. However, the role of HECTD3 expression in breast cancer prognosis has not yet been demonstrated.
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Yingying Wu, Fubing Li, Hailin Zhang, Dingyun You, Yanjie Kong, Zhongmei Zhou, Songqing Fan, Ceshi Chen (2026). HECTD3 is overexpressed in breast cancer and associated with a good prognosis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025073
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Frequently Asked Questions
What is HECTD3?
HECTD3 is an E3 ubiquitin ligase that plays a role in protein ubiquitination and has been implicated in cancer progression.
How is HECTD3 expression related to breast cancer prognosis?
High HECTD3 expression is associated with favorable prognostic factors such as lower lymph node metastasis, better tumor differentiation, and smaller tumor size, indicating a good prognosis.
What methods were used in this study?
Immunohistochemical staining was performed on breast cancer tissue samples and tissue microarrays to assess HECTD3 protein expression, followed by logistic regression analysis to correlate expression with clinicopathological parameters.
What are the key findings of this study?
HECTD3 is overexpressed in a majority of breast cancer cases, and its expression is significantly associated with lower risk of lymph node metastasis, reduced risk of poor differentiation, and smaller tumor size, suggesting it could serve as a prognostic biomarker.
What is the significance of this study?
The study provides evidence that HECTD3 may be a useful prognostic marker in breast cancer, potentially guiding treatment decisions and patient management.
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