Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer
Chemoresistance has been a major challenge in the treatment of patients with breast cancer. The diverse omics platforms and small sample sizes reported in the current studies of chemoresistance in breast cancer limit the consensus regarding the underlying molecular mechanisms of chemoresistance and...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/19/4878 |
| _version_ | 1797480128482115584 |
|---|---|
| author | Yang Huo Shuai Shao Enze Liu Jin Li Zhen Tian Xue Wu Shijun Zhang Daniel Stover Huanmei Wu Lijun Cheng Lang Li |
| author_facet | Yang Huo Shuai Shao Enze Liu Jin Li Zhen Tian Xue Wu Shijun Zhang Daniel Stover Huanmei Wu Lijun Cheng Lang Li |
| author_sort | Yang Huo |
| collection | DOAJ |
| description | Chemoresistance has been a major challenge in the treatment of patients with breast cancer. The diverse omics platforms and small sample sizes reported in the current studies of chemoresistance in breast cancer limit the consensus regarding the underlying molecular mechanisms of chemoresistance and the applicability of these study findings. Therefore, we built two transcriptome datasets for patients with chemotherapy-resistant breast cancers—one comprising paired transcriptome samples from 40 patients before and after chemotherapy and the second including unpaired samples from 690 patients before and 45 patients after chemotherapy. Subsequent conventional pathway analysis and new subpathway analysis using these cohorts uncovered 56 overlapping upregulated genes (false discovery rate [FDR], 0.018) and 36 downregulated genes (FDR, 0.016). Pathway analysis revealed the activation of several pathways in the chemotherapy-resistant tumors, including those of drug metabolism, MAPK, ErbB, calcium, cGMP-PKG, sphingolipid, and PI3K-Akt, as well as those activated by Cushing’s syndrome, human papillomavirus (HPV) infection, and proteoglycans in cancers, and subpathway analysis identified the activation of several more, including fluid shear stress, Wnt, FoxO, ECM-receptor interaction, RAS signaling, Rap1, mTOR focal adhesion, and cellular senescence (FDR < 0.20). Among these pathways, those associated with Cushing’s syndrome, HPV infection, proteoglycans in cancer, fluid shear stress, and focal adhesion have not yet been reported in breast cancer chemoresistance. Pathway and subpathway analysis of a subset of triple-negative breast cancers from the two cohorts revealed activation of the identical chemoresistance pathways. |
| first_indexed | 2024-03-09T21:55:24Z |
| format | Article |
| id | doaj.art-141341a3d4e545119595eff06b4246c6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:55:24Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-141341a3d4e545119595eff06b4246c62023-11-23T19:58:07ZengMDPI AGCancers2072-66942022-10-011419487810.3390/cancers14194878Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast CancerYang Huo0Shuai Shao1Enze Liu2Jin Li3Zhen Tian4Xue Wu5Shijun Zhang6Daniel Stover7Huanmei Wu8Lijun Cheng9Lang Li10School of Informatics, Indiana University, Indianapolis, IN 46032, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Medicine, School of Medicine, Indiana University, Indianapolis, IN 46032, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USADivision of Medical Oncology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Health Service Administration and Policy, College of Public Health, Temple University, Philadelphia, PA 19122, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USAChemoresistance has been a major challenge in the treatment of patients with breast cancer. The diverse omics platforms and small sample sizes reported in the current studies of chemoresistance in breast cancer limit the consensus regarding the underlying molecular mechanisms of chemoresistance and the applicability of these study findings. Therefore, we built two transcriptome datasets for patients with chemotherapy-resistant breast cancers—one comprising paired transcriptome samples from 40 patients before and after chemotherapy and the second including unpaired samples from 690 patients before and 45 patients after chemotherapy. Subsequent conventional pathway analysis and new subpathway analysis using these cohorts uncovered 56 overlapping upregulated genes (false discovery rate [FDR], 0.018) and 36 downregulated genes (FDR, 0.016). Pathway analysis revealed the activation of several pathways in the chemotherapy-resistant tumors, including those of drug metabolism, MAPK, ErbB, calcium, cGMP-PKG, sphingolipid, and PI3K-Akt, as well as those activated by Cushing’s syndrome, human papillomavirus (HPV) infection, and proteoglycans in cancers, and subpathway analysis identified the activation of several more, including fluid shear stress, Wnt, FoxO, ECM-receptor interaction, RAS signaling, Rap1, mTOR focal adhesion, and cellular senescence (FDR < 0.20). Among these pathways, those associated with Cushing’s syndrome, HPV infection, proteoglycans in cancer, fluid shear stress, and focal adhesion have not yet been reported in breast cancer chemoresistance. Pathway and subpathway analysis of a subset of triple-negative breast cancers from the two cohorts revealed activation of the identical chemoresistance pathways.https://www.mdpi.com/2072-6694/14/19/4878breast cancer chemotherapy resistancepathway analysistranscriptome |
| spellingShingle | Yang Huo Shuai Shao Enze Liu Jin Li Zhen Tian Xue Wu Shijun Zhang Daniel Stover Huanmei Wu Lijun Cheng Lang Li Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer Cancers breast cancer chemotherapy resistance pathway analysis transcriptome |
| title | Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer |
| title_full | Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer |
| title_fullStr | Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer |
| title_full_unstemmed | Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer |
| title_short | Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer |
| title_sort | subpathway analysis of transcriptome profiles reveals new molecular mechanisms of acquired chemotherapy resistance in breast cancer |
| topic | breast cancer chemotherapy resistance pathway analysis transcriptome |
| url | https://www.mdpi.com/2072-6694/14/19/4878 |
| work_keys_str_mv | AT yanghuo subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT shuaishao subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT enzeliu subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT jinli subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT zhentian subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT xuewu subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT shijunzhang subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT danielstover subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT huanmeiwu subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT lijuncheng subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer AT langli subpathwayanalysisoftranscriptomeprofilesrevealsnewmolecularmechanismsofacquiredchemotherapyresistanceinbreastcancer |