Proteasome ubiquitin receptor PSMD4 is an amplification target in breast cancer and may predict sensitivity to PARPi

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair under investigation as a chemotherapeutic target. Current randomized phase three trials of PARPi in metastatic breast cancer are limited to patients with documented BRCA1/2 mutations and no biomarker of PARPi beyond BRCA status is available. In an effort to identify novel biomarkers for PARP inhibition, we created a cell line (HCC1187/TALRES) resistant to the PARP1 inhibitor talazoparib. Herein we show by array-CGH that HCC1187/TALRES has a selective loss of the proteasome ubiquitin receptor PSMD4 amplicon resulting in significant down-regulation of PSMD4. Conversely, we find that breast cancer cell lines that have copy number gain or amplification for PSMD4 are significantly more sensitive to talazoparib. Functional studies reveal that knock-down of PSMD4 in amplified breast cancer cells and loss of the PSMD4 amplicon result in knock-down of PARP1 protein. We show that PSMD4 is amplified and overexpressed in breast cancer and its overexpression correlates with poor survival. Knock-down of PSMD4 results in a significant decrease in cell growth. We provide evidence that PSMD4 is a proteasomal amplification target in breast cancer that PSMD4 amplification confers sensitivity to PARP inhibition, and that PSMD4 amplification is lost in the process of acquiring resistance to PARPi. Finally, this study shows not only that PSMD4 copy number correlates with PARPi sensitivity, but also, that it may be a better predictor of sensitivity to PARPi than BRCA1/2 mutation.

PSMD4 regulates the malignancy of esophageal cancer cells by suppressing endoplasmic reticulum stress

“…During the course of tumor development, the metabolic pathway of protein metabolism is often disordered, and intracellular homeostasis is disrupted . It has been reported that PSMD4 plays an important role in ubiquitination‐related protein metabolism . Studies of patients with multiple myeloma have found that PSMD4 may be associated with adverse outcomes and resistance to bortezomib.…”

“…Studies of patients with multiple myeloma have found that PSMD4 may be associated with adverse outcomes and resistance to bortezomib. Additionally, PSMD4 is found to be amplified and overexpressed in breast cancer . However, few studies have been carried out on the expression and role of PSMD4 in EC.…”

“…PSMD4 not only plays a role in the regulation of ubiquitin protein degradation, but also participates in the development of biological processes . Abnormal expression of PSMD4 has been widely identified in different cancers . For instance, in breast cancer, PSMD4 is shown to be increased and upregulation of PSMD4 is correlated with poor survival .…”

“…1,2 According to the WHO histological classification, EC mainly comprises squamous cell carcinoma (SCC) and esophageal adenocarcinoma, of which the proportion of SCCs is as high as 90%. 3,4 In China, it is estimated that the average annual death total due to EC is~150 thousand people, which accounts for 21.8% of all cancer mortalities. 5 Among the leading causes of death, EC ranks fourth, with an average annual incidence of 17/1 000 000.…”

“…20 Abnormal expression of PSMD4 has been widely identified in different cancers. 18,21,22 For instance, in breast cancer, PSMD4 is shown to be increased and upregulation of PSMD4 is correlated with poor survival. 21 In colorectal cancer, PSMD4 is suggested to be a potential target for inhibiting tumor aggressiveness.…”