Hsa-mir-3163 and CCNB1 may be potential biomarkers and therapeutic targets for androgen receptor positive triple-negative breast cancer

Breast cancer (BC) is the most common malignancy in female, but the role of androgen receptor (AR) in triple-negative breast cancer (TNBC) is still unclear. This study aimed to exam the performance of innovative biomarkers for AR positive TNBC in diagnosis and therapies. Four datasets (GSE42568, GSE45827, GSE54002 and GSE76124) were analyzed by bioinformatic methods and the differential expression genes (DEGs) between the AR positive TNBC tissues and normal tissues were firstly identified by limma package and Venn diagrams. Next, Gene Ontologies (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the relationship between these DEGs. Then, the Protein-protein interaction (PPI) network was constructed. CytoHubba and bioinformatic approaches including Molecular Complex Detection (MCODE), Gene Expression Profiling Interactive Analysis (GEPIA), the Kaplan–Meier (KM) plotter and The Human Pro-tein Atlas (THPA) were used to identify the hub genes. Lastly, a miRNA-hub-gene regulatory axis was constructed by use of Target Scan database and ENCORI database. As a result, a total of 390 common DEGs were identified, including 250 up-regulated and 140 down-regulated. GO and KEGG enrichment analysis showed that the up-regulated DEGs were mostly enriched in the cell division, mitotic nuclear division, nucleosome, midbody, protein heterodimerization activity, cadherin binding involved in cell−cell adhesion, systemic lupus erythematosus and alcoholism, while the down-regulated DEGs were mainly enriched in carbohydrate metabolic process, extracellular space, extracellular region, zinc ion binding and microRNAs in cancer. Then, 13 hub genes (CCNB2, FOXM1, HMMR, MAD2L1, RRM2, TPX2, TYMS, CEP55, AURKA, CCNB1, CDK1, TOP2A, PBK) were selected. The survival analysis revealed that only CCNB1 was associated with significantly poor survival (P <0.05) in TNBC patients. Finally, we found that hsa-miR-3163 took part in the regulation of CCNB1 and constructed a potential hsa-miR-3163-CCNB1 regulatory axis. The results of current study suggest that CCNB1 and hsa-miR-3163 may serve as highly potential prognostic markers and therapeutic targets for AR positive TNBC. Our findings may make contributions to the diagnosis and therapies of AR positive TNBC.

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Exploring specific prognostic biomarkers in triple-negative breast cancer

Cell Death and Disease ◽

10.1038/s41419-019-2043-x ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 6

Author(s):

Chang Bao ◽

Yunkun Lu ◽

Jishun Chen ◽

Danni Chen ◽

Weiyang Lou ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Target Genes ◽

Triple Negative ◽

Therapeutic Targets ◽

Good Prognosis ◽

The Cancer Genome Atlas ◽

Prognostic Biomarkers ◽

Luciferase Reporter ◽

Hub Genes

Abstract Lacking of both prognostic biomarkers and therapeutic targets, triple-negative breast cancer (TNBC) underscores pivotal needs to uncover novel biomarkers and viable therapies. MicroRNAs have broad biological functions in cancers and may serve as ideal biomarkers. In this study, by data mining of the Cancer Genome Atlas database, we screened out 4 differentially-expressed microRNAs (DEmiRNAs) between TNBC and normal samples: miR-135b-5p, miR-9-3p, miR-135b-3p and miR-455-5p. They were specially correlated with the prognosis of TNBC but not non-TNBC. The weighted correlation network analysis (WGCNA) for potential target genes of 3 good prognosis-related DEmiRNAs (miR-135b-5p, miR-9-3p, miR-135b-3p) identified 4 hub genes with highly positive correlation with TNBC subtype: FOXC1, BCL11A, FAM171A1 and RGMA. The targeting relationships between miR-9-3p and FOXC1/FAM171A1, miR-135b-3p and RGMA were validated by dual-luciferase reporter assays. Importantly, the regulatory functions of 4 DEmiRNAs and 3 verified target genes on cell proliferation and migration were explored in TNBC cell lines. In conclusion, we shed lights on these 4 DEmiRNAs (miR-135b-5p, miR-9-3p, miR-135b-3p, miR-455-5p) and 3 hub genes (FOXC1, FAM171A1, RGMA) as specific prognostic biomarkers and promising therapeutic targets for TNBC.

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PI3K/AKT/mTOR pathway and androgen receptor expression as potential therapeutic targets for triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.e12069 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. e12069-e12069

Author(s):

Mirco Pistelli ◽

Zelmira Ballatore ◽

Mariagrazia De Lisa ◽

Arianna Della Mora ◽

Tommasina Biscotti ◽

...

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Targets ◽

Mtor Pathway ◽

Receptor Expression ◽

Androgen Receptor Expression

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Androgen receptor expression in triple-negative breast cancer

10.26226/morressier.596cd2b6d462b80292387085 ◽

2017 ◽

Author(s):

Ievgen Glavynskyi

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Receptor Expression ◽

Androgen Receptor Expression

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Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000443052 ◽

2016 ◽

Vol 38 (3) ◽

pp. 1003-1014 ◽

Cited By ~ 24

Author(s):

Aiyu Zhu ◽

Yan Li ◽

Wei Song ◽

Yumei Xu ◽

Fang Yang ◽

...

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Cyclin D1 ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

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