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Identification of RAD54 homolog B as a promising therapeutic target for breast cancer.

ABSTRACT: Breast cancer is a recognized threat to the health of women globally. Due to the lack of the knowledge about the molecular pathogenesis of breast cancer, therapeutic strategies remain inadequate, especially for aggressive breast cancer. In the present study, sequential bioinformatics analysis was performed using data from the GSE20711 dataset, and the results demonstrated that three genes may impact the survival of patients with breast cancer. One of these genes, RAD54 homolog B (RAD54B), may be a potential prognostic factor for breast cancer. A signature was established that could evaluate the overall survival for patients with breast cancer based on the risk score calculated from RAD54B expression and the Tumor-Node-Metastasis (TNM) stage [risk score=expRAD54B × 0.236 + TNM stage (I/II=0 or III/IV=1) ×1.025]. In addition, based on the GSE85871 dataset and inhibitory assay, the study identified a natural compound, Japonicone A, which may reduce the proliferation of breast cancer cells by inhibiting the expression of RAD54B. Overall, the present study identified a novel candidate gene and a candidate compound as promising therapeutic targets for the treatment of breast cancer.

SUBMITTER: Feng J

PROVIDER: S-EPMC6781656 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Identification of RAD54 homolog B as a promising therapeutic target for breast cancer.

Feng Jing J Hu Juanjuan J Xia Ying Y

Oncology letters 20190912 5

Breast cancer is a recognized threat to the health of women globally. Due to the lack of the knowledge about the molecular pathogenesis of breast cancer, therapeutic strategies remain inadequate, especially for aggressive breast cancer. In the present study, sequential bioinformatics analysis was performed using data from the GSE20711 dataset, and the results demonstrated that three genes may impact the survival of patients with breast cancer. One of these genes, RAD54 homolog B (RAD54B), may be ...[more]

PMID: 31612045

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Project description:BackgroundWe have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.MethodsRNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes.ResultsWe show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 × 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45α, and Ki67.ConclusionTogether, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy.

Dataset Information

Identification of RAD54 homolog B as a promising therapeutic target for breast cancer.

Publications

Identification of RAD54 homolog B as a promising therapeutic target for breast cancer.

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