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

Simple Summary Hormone therapy for breast cancer targets estrogen receptors to inhibit the growth of cancer cells. We previously reported that neural precursor cell-expressed developmentally downregulated 4-1 (NEDD4) promotes the degradation of the estrogen receptor alpha. Therefore, NEDD4 may affect the efficacy of hormone therapy and prognosis in hormone receptor-positive breast cancer patients. The prognosis of patients receiving perioperative neoadjuvant or adjuvant hormone therapy for 5-10 years could be particularly affected by NEDD4. This study revealed that patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer with low NEDD4 expression had a good outcome. Additionally, the association of NEDD4 with estrogen receptor alpha in breast cancer cells was also investigated to reveal the biological mechanisms that influenced clinical results. NEDD4 expression appears to be a predictive factor of the response to hormone therapy. Neural precursor cell-expressed developmentally downregulated 4-1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor alpha. 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 (p = 0.048 and p = 0.022, respectively). Western blotting revealed a high expression of estrogen receptor alpha 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 alpha 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.

Automated summary

Hormone therapy targeting estrogen receptors is used to inhibit the growth of breast cancer cells. This study investigates the role of NEDD4 in hormone therapy and prognosis in hormone receptor-positive breast cancer patients. Patients with low NEDD4 expression have a good prognosis, and NEDD4 expression may be a predictive factor for the response to hormone therapy.