Despite advances in treatment, breast cancer remains the most common malignant tumor in women worldwide, with the highest rate of increase in prevalence. The understanding of breast cancer's molecular pathways is critical for its diagnosis, treatment, and prognosis. The use of DNA microarray gene expression profiles to investigate DEGs involved in cancer has yielded useful diagnostic and medical applications (Wang et al., 2019).
In the present study, three gene expression profile datasets (GSE71053, GSE61724, GSE36295) from the GEO database were retrieved and analyzed. The DEGs were identified using the 'limma' R package. The common DEGs were filtered out and 24 hub genes were identified. GO function and pathway enrichment analysis was performed to further analyze the mechanisms of action of these DEGs. These DEGs were associated with the GO BP terms such as cell division, mitotic nuclear division, kinesins, aurora B signaling, FOXM1 transcription network, signaling by aurora kinases, M phase, meiotic sister chromatid cohesion and centromeric, actomyosin contractile ring assembly, centrosome separation, mitotic spindle midzome assembly, regulation of mitotic centrosome separation and response to ATP binding, carbohydrate derivative binding, anion binding as molecular functions terms. Furthermore, the pathways of DEGs were mainly enriched in mitotic prometaphase, M phase, cell cycle, mitotic, and resolution of sister chromatid cohesion.
Of the 24 genes, SFRP1 (Secreted Frizzled Related Protein 1) gene that is closely associated with breast cancer Wnt signaling pathway was identified. One of the most essential mechanisms controlling cell physiologic activities such as division, multiplication, and adhesion is the Wnt/β-catenin signaling pathway (Baharudin et al., 2020). Wnt ligand bind to Frizzled proteins and lipoprotein receptor-related proteins 5 and 6 receptors initiates signaling in normal circumstances. Then, as a transcription cofactor with T-cell factor/lymphoid enhancer factor, β-catenin aggregates and modulates the transcription of genes involved such as c-myc and cyclin D1 (Clemenceau et al., 2020). Abnormal activation of the Wnt/β-catenin signaling pathway is a common occurrence in malignancy, and also the abnormal methylation state of Wnt antagonists including such Dickkopf proteins, Wnt inhibitory factor1, and SFRPs may contribute to it (Kazi et al., 2019). SFRP1, a member of the SFRP family, can inhibit Wnt/-catenin signaling by interfering with Wnt–receptor associations via an N-terminal cysteine-rich domain similar to Frizzled proteins. SFRP1 is hypermethylated and down-regulated in breast cancer (Wu et al., 2020). SFRP1 hypermethylation and downregulation are also associated with poor prognosis in breast tumors (Schäfer et al., 2019). Moreover, SFRP1 is associated with tumor chemotherapy, and some antitumor drugs inhibit cell growth through the re-expression of SFRP1. However, new research has revealed that SFRP1 may also be strongly expressed in carcinomas and enhance tumor development or migration, in breast cancer (van Schie et al., 2020).
Our study demonstrates that SFRP1 is down-regulated in breast cancer patients which were analyzed in GEPIA and bc-GenExMiner database. Kaplan–Meier analysis showed that patient’s low SFRP1 expression had significantly poorer survival rates. These findings imply that the level of SFRP1 expression can predict patient prognosis and could be used as a novel therapy target for personalized patient treatment. As a result, SFRP1 may be linked to breast cancer pathogenesis and could be used as a diagnostic biomarker for the disease.