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Proteasome 26S subunit PSMD1 regulates breast cancer cell growth through p53 protein degradation
Toshiyuki Okumura1,2, Kazuhiro Ikeda1, Takafumi Ujihira1,2
1Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
Abstract:
Endocrine therapy using antiestrogens and aromatase inhibitors is usually efficient to treat patients with hormone-sensitive breast cancer. Many patients with endocrine therapy, however, often acquire resistance. In the present study, we performed functional screening using short hairpin RNA library to dissect genes involved in antiestrogen tamoxifen resistance in MCF-7 breast cancer cells. We identified seven candidate genes that are associated with poor prognosis of breast cancer patients based on clinical dataset. The expression levels of six out of seven genes were higher in 4-hydroxytamoxifen (OHT) resistant MCF-7 (OHTR) cells compared with parental MCF-7 cells. Among the six selected genes, siRNA-mediated knockdown of PSMD1 and TSPAN12 markedly reduced the proliferation of OHTR cells. Notably, the knockdown of proteasome 26S subunit PSMD1 exhibited cell cycle arrest and the accumulation of p53 protein through inhibiting p53 protein degradation. In accordance with p53 accumulation, its target genes p21 and SFN were also upregulated by PSMD1 silencing. Taken together, PSMD1 was identified as a potential gene that plays a role in the development of tamoxifen resistance in breast cancer cells. These findings will provide a new insight for the mechanism underlying endocrine therapy resistance and a prognostic and therapeutic molecular target for advanced breast cancer.
Insights
Researchers identified PSMD1 as a key gene in tamoxifen resistance in breast cancer. Silencing PSMD1 halts cancer cell growth and may offer new therapeutic targets for endocrine therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Endocrine therapy is effective for hormone-sensitive breast cancer but resistance is common.
- Tamoxifen resistance significantly impacts patient outcomes.
- Understanding the genetic basis of resistance is crucial for developing new treatments.
Purpose of the Study:
- To identify genes involved in tamoxifen resistance in breast cancer cells.
- To explore the role of PSMD1 in endocrine therapy resistance.
- To evaluate PSMD1 as a potential prognostic and therapeutic target.
Main Methods:
- Functional screening using a short hairpin RNA library in MCF-7 breast cancer cells.
- Analysis of gene expression in tamoxifen-resistant cells (OHTR) versus parental cells.
- siRNA-mediated knockdown of candidate genes, including PSMD1 and TSPAN12.
- Assessment of cell proliferation, cell cycle, and p53 protein levels.
Main Results:
- Seven candidate genes associated with poor breast cancer prognosis were identified.
- Six of these genes showed higher expression in OHTR cells compared to parental MCF-7 cells.
- Knockdown of PSMD1 and TSPAN12 reduced OHTR cell proliferation.
- PSMD1 silencing led to cell cycle arrest and p53 accumulation by inhibiting its degradation, upregulating p21 and SFN.
Conclusions:
- PSMD1 plays a significant role in the development of tamoxifen resistance in breast cancer.
- PSMD1 acts by stabilizing p53, influencing cell cycle progression.
- PSMD1 represents a potential molecular target for overcoming endocrine therapy resistance in advanced breast cancer.