Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression
Abstract Background Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to es...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-10-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13058-020-01351-1 |
| _version_ | 1819052725705375744 |
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| author | Benjamin Heng Ayse A. Bilgin David B. Lovejoy Vanessa X. Tan Heloisa H. Milioli Laurence Gluch Sonia Bustamante Tharani Sabaretnam Pablo Moscato Chai K. Lim Gilles J. Guillemin |
| author_facet | Benjamin Heng Ayse A. Bilgin David B. Lovejoy Vanessa X. Tan Heloisa H. Milioli Laurence Gluch Sonia Bustamante Tharani Sabaretnam Pablo Moscato Chai K. Lim Gilles J. Guillemin |
| author_sort | Benjamin Heng |
| collection | DOAJ |
| description | Abstract Background Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. Methods To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively. Results We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Conclusions Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes. |
| first_indexed | 2024-12-21T12:24:24Z |
| format | Article |
| id | doaj.art-2339ab5edf5e4945b152f4b86d3c26f6 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-21T12:24:24Z |
| publishDate | 2020-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-2339ab5edf5e4945b152f4b86d3c26f62022-12-21T19:04:14ZengBMCBreast Cancer Research1465-542X2020-10-0122111410.1186/s13058-020-01351-1Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppressionBenjamin Heng0Ayse A. Bilgin1David B. Lovejoy2Vanessa X. Tan3Heloisa H. Milioli4Laurence Gluch5Sonia Bustamante6Tharani Sabaretnam7Pablo Moscato8Chai K. Lim9Gilles J. Guillemin10Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie UniversityFaculty of Sciences and Engineering, Macquarie UniversityDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie UniversityDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie UniversitySchool of Environmental and Life Sciences, The University of NewcastleThe Strathfield Breast CentreBioanalytical Mass Spectrometry Facility, University of New South WalesDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie UniversitySchool of Electrical Engineering and Life Sciences, The University of NewcastleDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie UniversityDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie UniversityAbstract Background Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. Methods To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively. Results We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Conclusions Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.http://link.springer.com/article/10.1186/s13058-020-01351-1Kynurenine pathwayBreast cancerBiomarkerImmune evasionTryptophan |
| spellingShingle | Benjamin Heng Ayse A. Bilgin David B. Lovejoy Vanessa X. Tan Heloisa H. Milioli Laurence Gluch Sonia Bustamante Tharani Sabaretnam Pablo Moscato Chai K. Lim Gilles J. Guillemin Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression Breast Cancer Research Kynurenine pathway Breast cancer Biomarker Immune evasion Tryptophan |
| title | Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression |
| title_full | Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression |
| title_fullStr | Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression |
| title_full_unstemmed | Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression |
| title_short | Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression |
| title_sort | differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes beyond ido1 induced immunosuppression |
| topic | Kynurenine pathway Breast cancer Biomarker Immune evasion Tryptophan |
| url | http://link.springer.com/article/10.1186/s13058-020-01351-1 |
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