CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer
Currently, breast cancer (BRCA) has become the most common cancer in the world, whose pathological mechanism is complex. Among its subtypes, triple-negative breast cancer (TNBC) has the worst prognosis. With the increasing number of diagnosed TNBC patients, the urgent need of novel biomarkers is als...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.970950/full |
| _version_ | 1798040071406878720 |
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| author | Tianyi Cheng Yingyi Wu Yingyi Wu Zhiyu Liu Yi Yu Shixue Sun Min Guo Baoqing Sun Chen Huang Chen Huang |
| author_facet | Tianyi Cheng Yingyi Wu Yingyi Wu Zhiyu Liu Yi Yu Shixue Sun Min Guo Baoqing Sun Chen Huang Chen Huang |
| author_sort | Tianyi Cheng |
| collection | DOAJ |
| description | Currently, breast cancer (BRCA) has become the most common cancer in the world, whose pathological mechanism is complex. Among its subtypes, triple-negative breast cancer (TNBC) has the worst prognosis. With the increasing number of diagnosed TNBC patients, the urgent need of novel biomarkers is also rising. Cyclin-dependent kinase inhibitor 2A (CDKN2A) has recently emerged as a key regulator associated with ferroptosis and cuproptosis (FAC) and has exhibited a significant effect on BRCA, but its detailed mechanism remains elusive. Herein, we conducted the first converge comprehensive landscape analysis of FAC-related gene CDKN2A in BRCA and disclosed its prognostic value in BRCA. Then, an unsupervised cluster analysis based on CDKN2A-correlated genes unveiled three subtypes, namely cold-immune subtype, IFN-γ activated subtype and FTL-dominant subtype. Subsequent analyses depicting hallmarks of tumor microenvironment (TME) among three subtypes suggested strong association between TNBC and CDKN2A. Given the fact that the most clinically heterogeneous TNBC always displayed the most severe outcomes and lacked relevant drug targets, we further explored the potential of immunotherapy for TNBC by interfering CDKN2A and constructed the CDKN2A-derived prognostic model for TNBC patients by Lasso-Cox. The 21-gene–based prognostic model showed high accuracy and was verified in external independent validation cohort. Moreover, we proposed three drugs for TNBC patients based on our model via targeting epidermal growth factor receptor. In summary, our study indicated the potential of CDKN2A as a pioneering prognostic predictor for TNBC and provided a rationale of immunotherapy for TNBC, and offered fresh perspectives and orientations for cancer treatment via inducing ferroptosis and cuproptosis to develop novel anti-cancer treatment strategies. |
| first_indexed | 2024-04-11T22:02:26Z |
| format | Article |
| id | doaj.art-b252358f62134a81ba197617c9f262fa |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T22:02:26Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b252358f62134a81ba197617c9f262fa2022-12-22T04:00:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.970950970950CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancerTianyi Cheng0Yingyi Wu1Yingyi Wu2Zhiyu Liu3Yi Yu4Shixue Sun5Min Guo6Baoqing Sun7Chen Huang8Chen Huang9Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macao, Macao SAR, ChinaFaculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macao, Macao SAR, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao, Macao SAR, ChinaFaculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macao, Macao SAR, ChinaFaculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macao, Macao SAR, ChinaGuangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaGuangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, ChinaDepartment of Allergy and Clinical Immunology, Department of Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaFaculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macao, Macao SAR, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao, Macao SAR, ChinaCurrently, breast cancer (BRCA) has become the most common cancer in the world, whose pathological mechanism is complex. Among its subtypes, triple-negative breast cancer (TNBC) has the worst prognosis. With the increasing number of diagnosed TNBC patients, the urgent need of novel biomarkers is also rising. Cyclin-dependent kinase inhibitor 2A (CDKN2A) has recently emerged as a key regulator associated with ferroptosis and cuproptosis (FAC) and has exhibited a significant effect on BRCA, but its detailed mechanism remains elusive. Herein, we conducted the first converge comprehensive landscape analysis of FAC-related gene CDKN2A in BRCA and disclosed its prognostic value in BRCA. Then, an unsupervised cluster analysis based on CDKN2A-correlated genes unveiled three subtypes, namely cold-immune subtype, IFN-γ activated subtype and FTL-dominant subtype. Subsequent analyses depicting hallmarks of tumor microenvironment (TME) among three subtypes suggested strong association between TNBC and CDKN2A. Given the fact that the most clinically heterogeneous TNBC always displayed the most severe outcomes and lacked relevant drug targets, we further explored the potential of immunotherapy for TNBC by interfering CDKN2A and constructed the CDKN2A-derived prognostic model for TNBC patients by Lasso-Cox. The 21-gene–based prognostic model showed high accuracy and was verified in external independent validation cohort. Moreover, we proposed three drugs for TNBC patients based on our model via targeting epidermal growth factor receptor. In summary, our study indicated the potential of CDKN2A as a pioneering prognostic predictor for TNBC and provided a rationale of immunotherapy for TNBC, and offered fresh perspectives and orientations for cancer treatment via inducing ferroptosis and cuproptosis to develop novel anti-cancer treatment strategies.https://www.frontiersin.org/articles/10.3389/fimmu.2022.970950/fullcuproptosisimmunotherapytumor microenvironmenttriple-negative breast cancercyclin-dependent kinase inhibitor 2A |
| spellingShingle | Tianyi Cheng Yingyi Wu Yingyi Wu Zhiyu Liu Yi Yu Shixue Sun Min Guo Baoqing Sun Chen Huang Chen Huang CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer Frontiers in Immunology cuproptosis immunotherapy tumor microenvironment triple-negative breast cancer cyclin-dependent kinase inhibitor 2A |
| title | CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer |
| title_full | CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer |
| title_fullStr | CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer |
| title_full_unstemmed | CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer |
| title_short | CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer |
| title_sort | cdkn2a mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple negative breast cancer |
| topic | cuproptosis immunotherapy tumor microenvironment triple-negative breast cancer cyclin-dependent kinase inhibitor 2A |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.970950/full |
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