Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment
Abstract Background Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin-related...
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BMC
2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06559-3 |
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| author | Stephanie M. Wilk Kihak Lee Caitlyn C. Castillo Mohamed Haloul Alexa M. Gajda Virgilia Macias Elizabeth L. Wiley Zhengjia Chen Xinyi Liu Xiaowei Wang Maria Sverdlov Kent F. Hoskins Ekrem Emrah Er |
| author_facet | Stephanie M. Wilk Kihak Lee Caitlyn C. Castillo Mohamed Haloul Alexa M. Gajda Virgilia Macias Elizabeth L. Wiley Zhengjia Chen Xinyi Liu Xiaowei Wang Maria Sverdlov Kent F. Hoskins Ekrem Emrah Er |
| author_sort | Stephanie M. Wilk |
| collection | DOAJ |
| description | Abstract Background Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin-related transcription factors A and B (MRTFA/B also known as MKL1/2) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we investigated the expression and activation of these transcription factors to better assess their tumorigenic and metastatic impact on breast cancer and cells of the tumor microenvironment. Methods We used a multiplexed immunofluorescence approach to label MRTFA, MRTFB, tumor cells by using pan Cytokeratin, endothelial cells by using CD31, and antigen presenting cells (APCs) by using HLA-DRA on two different breast cancer tissue microarrays (TMA): The breast cancer progression TMA provided by the Cooperative Human Tissue Network (CHTN_BrCaProg3) and the University of Illinois Breast Cancer Working Group (TMA BCWG UIC-001-TMA) that included primary tumor and lymph node metastases from patients residing in the West Side and South Side of Chicago. We also used bioinformatics analyses of the TCGA and METABRIC databases and the Broad Institute’s single-cell RNA sequencing portal to investigate MRTFA/B expression patterns in the cells of the tumor microenvironment (TME). Results We found that in human tumors, MRTFA/B are concurrently activated in cancer cells, but they show distinct patterns of expression across different histological subtypes and in the cells of the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen-presenting cells (APCs), which has been previously associated with immune suppression and breast cancer progression. We also found that MRTFA expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR) in the TCGA data and found that MRTFA activity promotes VSIR expression in THP-1 monocytes and cultured HEK293 cells. Conclusions Our results provide unique insights into how MRTFA and MRTFB promote metastasis in human cancer, the differences of their expression patterns, and their immune suppressive function within the breast cancer TME. Our results will guide future studies on targeting MRTFA/B transcriptional activity and the resulting immune suppression in breast cancer. Graphical Abstract |
| format | Article |
| id | doaj-art-bdfa5973ba3c4e13900b580fa1c441f7 |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-05-01 |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-bdfa5973ba3c4e13900b580fa1c441f72025-08-20T02:00:03ZengBMCJournal of Translational Medicine1479-58762025-05-0123111910.1186/s12967-025-06559-3Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironmentStephanie M. Wilk0Kihak Lee1Caitlyn C. Castillo2Mohamed Haloul3Alexa M. Gajda4Virgilia Macias5Elizabeth L. Wiley6Zhengjia Chen7Xinyi Liu8Xiaowei Wang9Maria Sverdlov10Kent F. Hoskins11Ekrem Emrah Er12Department of Physiology and Biophysics, College of Medicine, University of Illinois ChicagoDepartment of Physiology and Biophysics, College of Medicine, University of Illinois ChicagoDepartment of Physiology and Biophysics, College of Medicine, University of Illinois ChicagoDepartment of Physiology and Biophysics, College of Medicine, University of Illinois ChicagoDepartment of Physiology and Biophysics, College of Medicine, University of Illinois ChicagoDepartment of Pathology, University of Illinois ChicagoDepartment of Pathology, University of Illinois ChicagoDivision of Epidemiology and Biostatistics, School of Public Health, University of Illinois ChicagoDepartment of Pharmacology & Regenerative Medicine, College of Medicine, University of Illinois ChicagoDepartment of Pharmacology & Regenerative Medicine, College of Medicine, University of Illinois ChicagoResearch Histology Core, Research Resources Center, University of Illinois ChicagoDivision of Hematology/Oncology, College of Medicine, University of Illinois ChicagoDepartment of Physiology and Biophysics, College of Medicine, University of Illinois ChicagoAbstract Background Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin-related transcription factors A and B (MRTFA/B also known as MKL1/2) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we investigated the expression and activation of these transcription factors to better assess their tumorigenic and metastatic impact on breast cancer and cells of the tumor microenvironment. Methods We used a multiplexed immunofluorescence approach to label MRTFA, MRTFB, tumor cells by using pan Cytokeratin, endothelial cells by using CD31, and antigen presenting cells (APCs) by using HLA-DRA on two different breast cancer tissue microarrays (TMA): The breast cancer progression TMA provided by the Cooperative Human Tissue Network (CHTN_BrCaProg3) and the University of Illinois Breast Cancer Working Group (TMA BCWG UIC-001-TMA) that included primary tumor and lymph node metastases from patients residing in the West Side and South Side of Chicago. We also used bioinformatics analyses of the TCGA and METABRIC databases and the Broad Institute’s single-cell RNA sequencing portal to investigate MRTFA/B expression patterns in the cells of the tumor microenvironment (TME). Results We found that in human tumors, MRTFA/B are concurrently activated in cancer cells, but they show distinct patterns of expression across different histological subtypes and in the cells of the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen-presenting cells (APCs), which has been previously associated with immune suppression and breast cancer progression. We also found that MRTFA expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR) in the TCGA data and found that MRTFA activity promotes VSIR expression in THP-1 monocytes and cultured HEK293 cells. Conclusions Our results provide unique insights into how MRTFA and MRTFB promote metastasis in human cancer, the differences of their expression patterns, and their immune suppressive function within the breast cancer TME. Our results will guide future studies on targeting MRTFA/B transcriptional activity and the resulting immune suppression in breast cancer. Graphical Abstracthttps://doi.org/10.1186/s12967-025-06559-3Myocardin related transcription factorsMRTFAMRTFBMALSRFMKL1 |
| spellingShingle | Stephanie M. Wilk Kihak Lee Caitlyn C. Castillo Mohamed Haloul Alexa M. Gajda Virgilia Macias Elizabeth L. Wiley Zhengjia Chen Xinyi Liu Xiaowei Wang Maria Sverdlov Kent F. Hoskins Ekrem Emrah Er Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment Journal of Translational Medicine Myocardin related transcription factors MRTFA MRTFB MAL SRF MKL1 |
| title | Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment |
| title_full | Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment |
| title_fullStr | Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment |
| title_full_unstemmed | Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment |
| title_short | Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment |
| title_sort | multiplex imaging reveals novel patterns of mrtfa b activation in the breast cancer microenvironment |
| topic | Myocardin related transcription factors MRTFA MRTFB MAL SRF MKL1 |
| url | https://doi.org/10.1186/s12967-025-06559-3 |
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