Jul 20, 2021
Research square preprints
Background : Neural precursor cell expressed developmentally downregulated 4 1 (NEDD4) is an E3 ligase that leads to the degradation of proteins including estrogen receptor a (ER). The E3 ligase can be a predictive marker of response to hormone therapy. We evaluated whether the expression level of NEDD4 affects the prognosis of hormone receptor positive breast cancer patients. To support our clinical results, the association of NEDD4 with ER in breast cancer cells was studied.Method : We performed a retrospective cohort study enrolling 145 patients with hormone receptor positive HER2 negative breast cancer with pathological stage 0-II. Their expression levels of NEDD4 mRNA were measured, and disease free survival (DFS) and overall survival (OS) were evaluated. Additionally, we knocked down NEDD4 in ER positive breast cancer cells, MCF 7. We evaluated the expression level of ER in the cells and sensitivity to hormone therapy.Result : Mean follow up time was 6.2 years. Of 67 patients with high NEDD4 levels (high NEDD4 group) and 78 patients with low NEDD4 levels (low NEDD4 group), 97.0% and 94.9% of the patients received neoadjuvant/adjuvant hormone therapy, respectively. The hormone therapy included aromatase inhibitors and tamoxifen. DFS and OS of the low NEDD4 group were significantly longer than the high NEDD4 group (p = 0.049 and p = 0.023). Western blot revealed high ER expression in NEDD4 knockdown cells. Proliferation of NEDD4 knockdown cells without estradiol stimulation as a simulation of the aromatase inhibitor therapy was suppressed to 53.6% of that with estradiol stimulation, whereas proliferation of NEDD4 expressing cells was suppressed to only 76.9%. Proliferation of NEDD4 knockdown cells with exposure to estradiol and hydroxytamoxifen was suppressed to 57.9% of that without exposure to hydroxytamoxifen. In contrast, proliferation of NEDD4 expressing cells was suppressed to only 73.3%. Thus, these simulations of hormone therapy showed a significant decrease in proliferation of NEDD4 knockdown cells.Conclusion : Knockdown of NEDD4 in ER positive breast cancer cells resulted in ER accumulation and high sensitivity to hormone therapy. Hormone receptor positive breast cancer patients with low expression of NEDD4 had favorable DFS and OS.
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