E3 Ubiquitin Ligase NEDD4 Affects Estrogen Receptor α Expression and the Prognosis of Patients with Hormone Receptor-Positive Breast Cancer

Neural precursor cell-expressed developmentally downregulated 4-1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort s...

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Published in:Cancers 2023-01, Vol.15 (2), p.539
Main Authors: Natori, Yutaka, Suga, Junko, Tokuda, Emi, Tachibana, Kazunoshin, Imai, Jun-Ichi, Honma, Reiko, Azami, Yusuke, Noda, Masaru, Sasaki, Eisaku, Watanabe, Shinya, Ohtake, Tohru, Saji, Shigehira
Format: Article
Language:English
Subjects:
17β-Estradiol
Breast cancer
Cell culture
Cell growth
Cell proliferation
Cohort analysis
Endocrine therapy
Epidermal growth factor
Estrogen receptors
Estrogens
Kinases
Ligands
Medical prognosis
Medical records
mRNA
Prognosis
Proteins
Ubiquitin
Ubiquitin-protein ligase
Values
Western blotting
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Summary:Neural precursor cell-expressed developmentally downregulated 4-1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort study enrolling 143 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer. Of the 66 patients with high NEDD4 mRNA levels (high NEDD4 group) and 77 patients with low NEDD4 mRNA levels (low NEDD4 group), 98.4% and 96.1%, respectively, of the patients had received neoadjuvant/adjuvant hormone therapy. Disease-free survival and overall survival were significantly longer in the low NEDD4 group than in the high NEDD4 group ( = 0.048 and = 0.022, respectively). Western blotting revealed a high expression of estrogen receptor α in the NEDD4-knockdown culture cells. The proliferation of NEDD4-knockdown cells treated with tamoxifen or estradiol deprivation was suppressed, compared with that of NEDD4-expressing cells. Knockdown of NEDD4 in breast cancer cells induced the accumulation of estrogen receptor α and increased sensitivity to hormone therapy. In summary, this mechanism may lead to a better prognosis in hormone receptor-positive breast cancer patients with a low expression of NEDD4.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers15020539