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  • br response in tumor progression


     response in tumor progression, which may facilitate the invasion of tumor cells (McCart Reed et al., 2013). PPARGC1A was reported to promote breast cancer cell invasion and migration in vitro. Invasive cancer cells use PPARGC1A to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate (LeBleu et al., 2014). Clinical analysis of human invasive breast cancers showed that there was a strong correlation between PPARGC1A expression in invasive cancer cells and the formation of distant metastases (Andrzejewski et al., 2017). CREB5 has been identified to overexpress in several types of human cancer, including breast cancer. CREB5 plays crucial roles in regulating cell growth, prolif-eration, differentiation and CY7-SE regulation (He et al., 2017). COL5A3 encodes alpha chains of collagen type 5, up-regulation of which has been related to metastatic potential in carcinoma (Huang et al., 2017). We proposed that these expression changes could be involved in facilitating the proliferation of breast cancer cells and might thus mark a critical point in disease development.
    Gene ontology (GO) analysis showed that an extended number of biological processes and pathways were significantly enriched with the up and down-regulated genes by BPS exposure (Fig. 3). The representative altered biological processes and KEGG pathways as well as the involved core genes were listed in Table 3. In these processes, the PI3K-Akt signaling pathway regulates survival and proliferation capacity of cells. Aberrant activation of the pathway is commonly observed in many human cancers, including breast,
    Fig. 2. Unsupervised analysis of the RNA-sequencing samples. The principal component (PC) plot (A) and the heat map (B) showed that samples belonging to the same group tended to cluster together and BPS exposure group segregated apart from the control group.
    Fig. 3. Significantly altered biological processes and KEGG pathways in MCF-7 cells exposure to BPS by gene ontology analysis (FDR<0.1).
    Table 3
    Enriched biological processes/KEGG pathways and core genes in MCF-7 cells altered by BPS exposure.
    Biological process/KEGG pathway Count Core genes FDR
    lung, endometrial, and prostate. Alterations in this pathway have been reported to induce cell line proliferation, transformation and tumor formation in transgenic mice (Martini et al., 2014). Alter-ations in extracellular matrix may not only promotes the trans-formation and invasion of cancer cell, but also helps to create the microenvironment that further favors tumor progression (Cox and Erler, 2011; Lu et al., 2012; Soysal et al., 2015). According to previ-ously reported studies, BPS has estrogenic effects related to the development and progression of cancers in estrogen-responsive organs including breast (Rochester and Bolden, 2015). BPS can lead to the proliferation, migration, and epithelial mesenchymal transition of MCF-7 clonal variant breast cancer cells expressing estrogen receptors (Kim et al., 2017). In addition, BPS can induce migration of triple negative breast cancer cells (Deng et al., 2018). Therefore, dysregulation of these genes related to PI3K-Akt signaling pathway and extracellular matrix may facilitate the pro-liferation and development of breast cancer cells. All these results implied that BPS exposure might play a role in the progression of breast cancer.
    4. Conclusion
    In this work, we used several system biological methods to investigate whether BPS could induce epigenetic effects on human breast cancer cell line MCF-7. The obtained results showed that BPS could change DNA methylation level of transposons. Besides, methylation status in promoter of breast cancer related genes CDH1, SFN, TNFRSF10C were also changed, which implied that epigenetic changes induced by BPS might play a role in the devel-opment of breast cancer. Gene expression profiling and ontology analysis further suggested the influence of BPS on breast cancer, showing that BPS exposure upregulated the expression level of genes related to development of breast cancer, including THBS4, PPARGC1A, CREB5, COL5A. The significantly changed genes were enriched in extracellular matrix and PI3K-Akt signaling pathway 
    that contribute to development of breast cancer. These results can be taken as a hint for a breast cancer promoting potential of BPS. These findings broadened the understanding on the risk of BPS exposure and raised concerns on the safety using of BPS as the alternative for BPA. Regarding this topic, tumor models should be included in future studies.
    Appendix A. Supplementary data