| Breast cancer and ovarian cancer are the two most common malignant tumors in women that seriously endanger women's health and affect the quality of life of women.Although the treatment methods of breast cancer and ovarian cancer are continuously improving,they still cannot effectively reverse the trend of increasing morbidity and mortality year by year.The malignant progression,such as recurrence and metastasis after treatment,are the main reasons leading to short survival and poor prognosis of patients with breast and ovarian cancer.Although breast cancer and ovarian cancer are two different types of malignant tumors,they have the following characteristics in common:(1)similar genetic background,(2)similar pathophysiology,(3)both hormone-dependent tumors and so on,which suggest that there is a certain relationship between breast cancer and ovarian cancer.Also,hereditary breast cancer-ovarian cancer syndrome has become a more common family hereditary syndrome and this disease also shows the relationship between breast cancer and ovarian cancer.As one of the conventional methods for the treatment of breast and ovarian cancer,chemotherapy has a wide range of clinical applications.Chemotherapy drugs kill tumor cells through their cytotoxic effects.They are usually used as adjuvant therapy before and after surgery for patients with breast and ovarian cancer,or as conservative treatment methods for patients who cannot undergo surgery.However,previous studies have shown that,while killing tumor cells,chemotherapy may also promote their invasion into blood vessels and promote tumor metastasis.The current study has not yet explored the common markers related to breast cancer and ovarian cancer metastasis caused by chemotherapy from a systematic perspective.In order to explore such common potential markers,the related gene expression profiles of breast cancer and ovarian cancer patients were studied based on bioinformatics methods.Screening for differentially expressed genes before and after chemotherapy,analysis of enrichment pathways,construction of a weighted gene co-expressionnetwork,division of modules and selection of hub genes,literature validation and survival analysis were used to explore and predict the molecular mechanism of the effects of chemotherapy on breast and ovarian cancer.Objective:Here we used the breast cancer and ovarian cancer RNA-seq datasets in the GEO database to explore common genes related to breast cancer and ovarian cancer metastasis caused by chemotherapy based on differential gene expression analysis and weighted gene co-expression network analysis.It will provide theoretical basis and scientific basis for exploring the common molecular mechanism of breast cancer and ovarian cancer metastasis caused by chemotherapy,discovering new molecular markers and potential therapeutic targets,and improving the therapeutic effect of chemotherapy on these two common malignancies in women.Methods:Breast cancer-associated dataset GSE21974 and ovarian cancer-associated dataset GSE7463 from Gene Expression Omnibus(GEO)database were included.Differential expressed genes(DEGs)between pre-and post-chemotherapy samples of breast cancer patients and breast cancer patients were identified by Limma package of R software.After the identification of differentially expressed mRNAs,significant module was explored by using weighted gene coexpression network analysis(WGCNA)followed by functional enrichment analysis of the genes in the significant module.Finally,Weighted gene co-expression network was constructed to screen hub genes and reveal their potential pathways related to breast cancer and ovarian cancer.The Venny software was used to intersect the hub genes of breast cancer and the hub genes of ovarian cancer to obtain common hub genes.The biological significance of hub genes in metastasis was further explored through literature review and survival analysis.Finally,the KEGG enrichment analysis based on R software was used to explore the metabolic pathways involved in the in metastasis-related hub genes.Results:1.Expression changes of breast cancer-related genes and identification of hub genes after chemotherapy1656 differentially expressed genes were identified between post-chemotherapy and pre-chemotherapy samples of breast cancer patients,including 1110 up-regulated genes and 546 down-regulated genes.The DEGs were enriched in the biologicalprocesses such as cell cycle,PPAR signaling pathway,and focal adhesion.In the WGCNA,the DEGs were divided into five gene modules,and blue module had the strongest positive correlation with chemotherapy(r=0.64,P=5.0E-07).The genes in blue module were mainly enriched in PPAR signaling pathway,ECM-receptor interaction,protein digestion and absorption,focal adhesion,and tyrosine metabolism,indicating that the extracellular matrix dysfunction represents an essential component of breast cancer metastasis.Nineteen hub genes in blue module,eg VWF,AOC3,CAV1,JAM2,FXYD1,and SRPX,were identified and predicted that might play potential key roles in the process of chemotherapy-related breast cancer metastasis.2.Expression changes of ovarian cancer-related genes and identification of hub genes after chemotherapy916 differentially expressed genes were identified between post-chemotherapy and pre-chemotherapy samples of ovarian cancer patients,including 480 up-regulated genes and 436 down-regulated genes.The DEGs were enriched in the biological processes such as cell cycle,cellular senescence,and p53 signaling pathway.In the WGCNA,the DEGs were divided into four gene modules,and turquoise module had the strongest positive correlation with chemotherapy(r=0.75,P=6.0E-07).The genes in turquoise module were mainly enriched in focal adhesion,PI3K-Akt signaling pathway,mineral absorption,tyrosine metabolism and aldosterone synthesis and secretion.26 hub genes in turquoise module,eg JAM3,UST,NDN,EFEMP1 and CD302,were identified and predicted that might play potential key roles in the process of chemotherapy-related ovarian cancer metastasis.3.Selection of common genes and identification of their role in promoting metastasisUsing Venny software to intersect the hub genes of breast cancer-related and the differentially expressed genes between chemotherapy and non-chemotherapy samples of ovarian cancer,a total of six common genes were obtained,namely VWF,CAV1,SVEP1,FXYD1,PPAP2 B,and AOC3.The common genes were involved in tyrosine metabolism,proteoglycans in cancer,PI3K-Akt signaling pathway,focal adhesion,ECM-receptor interaction and complement and coagulation cascades.Based on the literature validation and survival analysis results,we predict that VWF,CAV1,SVEP1,FXYD1,and AOC3 may play potential roles in the process of chemotherapy-induced breast and ovarian cancer metastasis.Among them,FXYD1 was elected as a common hub gene of breast and ovarian cancer,indicating its key central regulatory role inpromoting metastasis.Conclusions:We identified several genes,i.g.FXYD1?VWF?SVEP1?CAV1?AOC3,and their relative pathways that were closely related to chemotherapy promoting breast cancer and ovarian cancer metastasis.The findings may help further elucidate the underlying mechanisms of chemotherapy pro-metastatic effects in breast and ovarian cancer and provide novel insights to research potential gene biomarkers and signaling pathways for treatment. |
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