Breast cancer is the most commonly diagnosed malignancy in women worldwide and is the main cause of cancer-related death in women [33–35]. Despite significant advances in cancer research, breast cancer remains a major health problem and is a top biomedical research priority [36–38], as there is an urgent need for effective breast cancer treatments.
In this study, we identified 10 significant genes (CLDN7, MLLT10, RBM33, SH3RF1, SSBP4, UBE2Z, BMPER, FGF7, MSRB3, and TNRC6B) in breast cancer using combined GWAS data and profiling of DEGs. Protein profiling in breast cancer samples from the HPA using immunohistochemistry and analysis of significant DEGs in breast cancer samples compared to normal samples from GEPIA further verified the results. Significantly overexpressed genes (CLDN7, MLLT10, RBM33, SH3RF1, SSBP4, and UBE2Z) were correlated with shorter survival, whereas underexpressed genes (BMPER, FGF7, MSRB3, and TNRC6B) were correlated with longer survival in breast cancer.
Consistent with our findings, previous studies have shown that some of these genes play important roles in the development of breast cancer. For example, Bernardi et al. [39] showed that CLDN7 is associated with a shorter time to recurrence, suggesting its contribution to the aggressiveness of breast cancer. In a GWAS, Guo et al. [40] identified common genetic loci for breast cancer risk including SSBP4. Whole transcriptome analysis by Bauer et al. [41] demonstrated that BMPER plays a possible therapeutic role in breast cancer. Fu et al. [42] demonstrated that acetylation, expression and recruitment of FGF7 promoters induce cancer growth and progression. Zhu et al. [43] found that targeting FGF7 can exert oncogenic functions in breast cancer. A previous study showed that the ZEB1-MSRB3 axis is related to breast cancer genome stability [44]. Interestingly, other DEGs in breast cancer identified in this study, including MLLT10, RBM33, SH3RF1, UBE2Z, and TNRC6B, have not been proven in previous studies. We believe that these are potentially novel key genes in breast cancer.
BP analysis in GO annotation indicated that the 10 significant genes are mainly enriched in the Wnt signaling pathway, which plays an important role in the occurrence and development of many cancers. Inhibiting this pathway can suppress breast cancer growth and metastasis [45–47]. MF analysis of GO suggested that the DEGs were most significantly enriched in functions related to oxidoreductase activity. The redox reaction is accompanied by tumor development. CC analysis of GO annotation showed that the 10 DEGs were enriched in P-bodies. A previous study suggested that P-body disassembly correlates with breast cancer progression [48].
KEGG analysis of the 10 DEGs showed their enrichment in breast cancer, gastric cancer, melanoma, the PI3K/Akt signaling pathway, MAPK signaling pathway, Ras signaling pathway, tight junctions, and ubiquitin-mediated proteolysis. Some of these pathways contribute to the development of breast cancer. For example, the PI3K pathway is found in many types of cancer and plays an important role in breast cancer cell proliferation [49]. Ras signaling is a key determinant of poor survival in breast cancer patients [50]. MAPK regulators are widely used for triple-negative breast cancer-targeted therapy. Abnormal MAPK signaling plays a core role in the regulation of growth and survival and the development of drug resistance in triple-negative breast cancer [51].
The aim of this work was to identify significant genes and potential therapeutic agents for breast cancer based on genomics. We found 65 potentially small molecule compounds to reverse significant genes in breast cancer. The 10 most significant drugs were trichostatin A, LY-294002, econazole, Prestwick-1082, vorinostat, lomefloxacin, clorsulon, amantadine, thiostrepton, and orciprenaline. Consistent, with our study, it has been reported that that trichostatin A, a histone deacetylase inhibitor, has therapeutic potential in breast cancer[52]. Jiang et al. [53] showed that trichostatin A sensitizes ER-negative breast cancer cells to tamoxifen. LY294002, a specific inhibitor of the PI3K pathway, can decrease the rate of cell growth and increase therapeutic sensitivity in MCF7 cells expressing wild-type p53, which may be useful for the treatment of breast cancer [54]. Econazole is a novel PI3K/AKT signaling pathway inhibitor, which can be used to overcome adriamycin resistance and improve chemotherapy sensitivity in breast cancer [55]. A preclinical study showed that vorinostat can prevent the formation of brain metastases in breast cancer [56]. Yang et al. [57] suggested that thiostrepton is a promising agent in triple-negative breast cancer. Kwok et al. [58] showed that thiostrepton selectively targets breast cancer cells through inhibition of Forkhead box M1 expression. However, some of the predicted drugs such as Prestwick-1082, lomefloxacin, clorsulon, amantadine, and orciprenaline have not been shown to directly play a role in breast cancer. Thus, future studies are needed to confirm our findings.
In conclusion, we conducted an analysis combining genomic data with drug database analysis to identify novel candidate therapeutic agents for breast cancer treatment. Our study demonstrates the usefulness of this approach for evaluating the relationship among genes, diseases, and drugs. These findings will pave the way for the discovery of potential therapeutic targets for breast cancer.