Abstract
It is well-known that human epidermal growth factor receptor 2 (HER2) is critical for breast cancer (BC) development and progression. Several studies have revealed the role of the ubiquitin/proteasome system (UPS) in cancer. In this study, we investigated the expression level of Proteasome 26S subunit, non-ATPase 3 (PSMD3) in BC using BC cell lines, human BC tissue samples, Oncomine, and TCGA databases and studied the PSMD3-HER2 protein interaction. PSMD3 was upregulated in BC, particularly in the HER2+ subtype. PSMD3 immunostaining was detected in the cytoplasm and nucleus of BC tumor tissues. Strong interaction between PSMD3 and HER2 at the protein level was observed. Knockdown of PSMD3 significantly impaired the stability of HER2, inhibited BC cell proliferation and colony formation, and induced cell apoptosis. Ubiquitination process was strongly enhanced after knockdown of PSMD3 in association with decreased HER2 level. Accumulation and Localization of LAMP-1 in the cell membrane with decreased HER2 immunostaining was observed after knockdown of PSMD3. High expression level of PSMD3 was associated with HER2 expression (p < 0.001), tumor size (p < 0.001), and clinical stage (p = 0.036). High expression level of PSMD3 predicted a short overall survival (OS), particularly for HER2+. Overall, we provide a novel function for PSMD3 in stabilizing HER2 from degradation in HER2+ BC, which suggests that PSMD3 is a novel target for HER2+ BC.
Highlights
Breast cancer (BC) is considered the most common malignancy affecting women worldwide and the second leading cause of death in women after lung cancer [1]
PCR amplification curves generated from tumor samples were shifted forward relative to curves generated from normal tissues, indicating relatively higher PSMD3 expression in tumor tissues
Group 2 included patients with a higher PSMD3 level in tumors tissues than in normal tissues (T > N, 153/176, 87%); the results indicated the upregulation of PSMD3 in tumor tissues
Summary
Breast cancer (BC) is considered the most common malignancy affecting women worldwide and the second leading cause of death in women after lung cancer [1]. BC has been classified based on variations in gene expression into four groups: basal-like group, ERBB2-overexpressing group, estrogen receptor (ER) group, and normal-like group, and these groups are highly related to prognosis and clinical outcome prediction [2,3]. It is known that HER2 overexpression accounts for 15–30% of BC patients with highly associated metastasis and poor clinical prognosis [6]. Trastuzumab (Herceptin) is a monoclonal antibody that has been proven to be effective to treat HER2+ BC, and treatment with Herceptin after adjuvant therapy is effective on OS [7,8,9]. Resistance to Trastuzumab in BC is a common problem despite the significant improvement in OS [10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
