Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer
Background: The progression of tumors from less aggressive subtypes to more aggressive states during metastasis poses challenges for treatment strategies. Previous studies have revealed the molecular subtype conversion between primary and metastatic tumors in breast cancer (BC). However, the subtype...
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MDPI AG
2024-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/3/678 |
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| author | Xiaoyan Zhang Fengyu Yang Zhijian Huang Xiaojun Liu Gan Xia Jieye Huang Yang Yang Junchen Li Jin Huang Yuxin Liu Ti Zhou Weiwei Qi Guoquan Gao Xia Yang |
| author_facet | Xiaoyan Zhang Fengyu Yang Zhijian Huang Xiaojun Liu Gan Xia Jieye Huang Yang Yang Junchen Li Jin Huang Yuxin Liu Ti Zhou Weiwei Qi Guoquan Gao Xia Yang |
| author_sort | Xiaoyan Zhang |
| collection | DOAJ |
| description | Background: The progression of tumors from less aggressive subtypes to more aggressive states during metastasis poses challenges for treatment strategies. Previous studies have revealed the molecular subtype conversion between primary and metastatic tumors in breast cancer (BC). However, the subtype conversion during lymph node metastasis (LNM) and the underlying mechanism remains unclear. Methods: We compared clinical subtypes in paired primary tumors and positive lymph nodes (PLNs) in BC patients and further validated them in the mouse model. Bioinformatics analysis and macrophage-conditioned medium treatment were performed to investigate the role of macrophages in subtype conversion. Results: During LNM, hormone receptors (HRs) were down-regulated, while HER2 was up-regulated, leading to the transformation of luminal A tumors towards luminal B tumors and from luminal B subtype towards HER2-enriched (HER2-E) subtype. The mouse model demonstrated the elevated levels of HER2 in PLN while retaining luminal characteristics. Among the various cells in the tumor microenvironment (TME), macrophages were the most clinically relevant in terms of prognosis. The treatment of a macrophage-conditioned medium further confirmed the downregulation of HR expression and upregulation of HER2 expression, inducing tamoxifen resistance. Through bioinformatics analysis, MNX1 was identified as a potential transcription factor governing the expression of HR and HER2. Conclusion: Our study revealed the HER2-E subtype conversion during LNM in BC. Macrophages were the crucial cell type in TME, inducing the downregulation of HR and upregulation of HER2, probably via MNX1. Targeting macrophages or MNX1 may provide new avenues for endocrine therapy and targeted treatment of BC patients with LNM. |
| first_indexed | 2024-03-08T03:59:16Z |
| format | Article |
| id | doaj.art-15654304b2704a7691c5d7d7a2b6379b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T03:59:16Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-15654304b2704a7691c5d7d7a2b6379b2024-02-09T15:09:33ZengMDPI AGCancers2072-66942024-02-0116367810.3390/cancers16030678Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast CancerXiaoyan Zhang0Fengyu Yang1Zhijian Huang2Xiaojun Liu3Gan Xia4Jieye Huang5Yang Yang6Junchen Li7Jin Huang8Yuxin Liu9Ti Zhou10Weiwei Qi11Guoquan Gao12Xia Yang13Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, ChinaBackground: The progression of tumors from less aggressive subtypes to more aggressive states during metastasis poses challenges for treatment strategies. Previous studies have revealed the molecular subtype conversion between primary and metastatic tumors in breast cancer (BC). However, the subtype conversion during lymph node metastasis (LNM) and the underlying mechanism remains unclear. Methods: We compared clinical subtypes in paired primary tumors and positive lymph nodes (PLNs) in BC patients and further validated them in the mouse model. Bioinformatics analysis and macrophage-conditioned medium treatment were performed to investigate the role of macrophages in subtype conversion. Results: During LNM, hormone receptors (HRs) were down-regulated, while HER2 was up-regulated, leading to the transformation of luminal A tumors towards luminal B tumors and from luminal B subtype towards HER2-enriched (HER2-E) subtype. The mouse model demonstrated the elevated levels of HER2 in PLN while retaining luminal characteristics. Among the various cells in the tumor microenvironment (TME), macrophages were the most clinically relevant in terms of prognosis. The treatment of a macrophage-conditioned medium further confirmed the downregulation of HR expression and upregulation of HER2 expression, inducing tamoxifen resistance. Through bioinformatics analysis, MNX1 was identified as a potential transcription factor governing the expression of HR and HER2. Conclusion: Our study revealed the HER2-E subtype conversion during LNM in BC. Macrophages were the crucial cell type in TME, inducing the downregulation of HR and upregulation of HER2, probably via MNX1. Targeting macrophages or MNX1 may provide new avenues for endocrine therapy and targeted treatment of BC patients with LNM.https://www.mdpi.com/2072-6694/16/3/678breast cancerclinical subtypeendocrine resistancemacrophageMNX1 |
| spellingShingle | Xiaoyan Zhang Fengyu Yang Zhijian Huang Xiaojun Liu Gan Xia Jieye Huang Yang Yang Junchen Li Jin Huang Yuxin Liu Ti Zhou Weiwei Qi Guoquan Gao Xia Yang Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer Cancers breast cancer clinical subtype endocrine resistance macrophage MNX1 |
| title | Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer |
| title_full | Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer |
| title_fullStr | Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer |
| title_full_unstemmed | Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer |
| title_short | Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer |
| title_sort | macrophages promote subtype conversion and endocrine resistance in breast cancer |
| topic | breast cancer clinical subtype endocrine resistance macrophage MNX1 |
| url | https://www.mdpi.com/2072-6694/16/3/678 |
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