CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling
Abstract Background Breast cancer, the most diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through sig...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-022-00926-z |
| _version_ | 1818497916595077120 |
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| author | Johnathan Abou-Fadel Xiaoting Jiang Brian Grajeda Akhil Padarti Cameron C. Ellis Esmeralda Flores Alyssa-Marie D. Cailing-De La O Jun Zhang |
| author_facet | Johnathan Abou-Fadel Xiaoting Jiang Brian Grajeda Akhil Padarti Cameron C. Ellis Esmeralda Flores Alyssa-Marie D. Cailing-De La O Jun Zhang |
| author_sort | Johnathan Abou-Fadel |
| collection | DOAJ |
| description | Abstract Background Breast cancer, the most diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through signaling cascades involving classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, CCM1-3, form the CCM signaling complex (CSC) which mediates multiple signaling cascades. Methods Utilizing molecular, cellular, Omics, and systems biology approaches, we analyzed the relationship among the CSC, PRG, and nPRs/mPRs during breast cancer tumorigenesis. Results We discovered that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them, forming the CmPn (CSC-mPRs-PRG-nPRs) signaling network. We found that mPR-specific PRG actions (PRG + MIF) play an essential role in this CmPn network during breast cancer tumorigenesis. Additionally, we have identified 4 categories of candidate biomarkers (9 intrinsic, 2 PRG-inducible, 1 PRG-repressive, 1 mPR-specific PRG-repressive, and 2 mPR-responsive) for Luminal-A breast cancers during tumorigenesis and have confirmed the prognostic application of RPL13 and RPL38 as intrinsic biomarkers using a dual validation method. Conclusions We have discovered that the CSC plays an essential role in the CmPn signaling network for Luminal-A breast cancers with identification of two intrinsic biomarkers. Video Abstract |
| first_indexed | 2024-12-10T18:51:26Z |
| format | Article |
| id | doaj.art-1562a5c5fdc6469b8bb60838712c70e5 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-10T18:51:26Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-1562a5c5fdc6469b8bb60838712c70e52022-12-22T01:37:18ZengBMCCell Communication and Signaling1478-811X2022-08-0120112210.1186/s12964-022-00926-zCCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signalingJohnathan Abou-Fadel0Xiaoting Jiang1Brian Grajeda2Akhil Padarti3Cameron C. Ellis4Esmeralda Flores5Alyssa-Marie D. Cailing-De La O6Jun Zhang7Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El PasoDepartment of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El PasoDepartment of Biological Sciences, University of Texas at El PasoDepartment of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El PasoDepartment of Biological Sciences, University of Texas at El PasoDepartment of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El PasoDepartment of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El PasoDepartment of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El PasoAbstract Background Breast cancer, the most diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through signaling cascades involving classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, CCM1-3, form the CCM signaling complex (CSC) which mediates multiple signaling cascades. Methods Utilizing molecular, cellular, Omics, and systems biology approaches, we analyzed the relationship among the CSC, PRG, and nPRs/mPRs during breast cancer tumorigenesis. Results We discovered that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them, forming the CmPn (CSC-mPRs-PRG-nPRs) signaling network. We found that mPR-specific PRG actions (PRG + MIF) play an essential role in this CmPn network during breast cancer tumorigenesis. Additionally, we have identified 4 categories of candidate biomarkers (9 intrinsic, 2 PRG-inducible, 1 PRG-repressive, 1 mPR-specific PRG-repressive, and 2 mPR-responsive) for Luminal-A breast cancers during tumorigenesis and have confirmed the prognostic application of RPL13 and RPL38 as intrinsic biomarkers using a dual validation method. Conclusions We have discovered that the CSC plays an essential role in the CmPn signaling network for Luminal-A breast cancers with identification of two intrinsic biomarkers. Video Abstracthttps://doi.org/10.1186/s12964-022-00926-zCerebral cavernous malformation (CCM)Signaling complex (CSC)Progesterone (PRG)Mifepristone (MIF)Prognostic biomarkersClassic nuclear progesterone receptors (nPRs) |
| spellingShingle | Johnathan Abou-Fadel Xiaoting Jiang Brian Grajeda Akhil Padarti Cameron C. Ellis Esmeralda Flores Alyssa-Marie D. Cailing-De La O Jun Zhang CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling Cell Communication and Signaling Cerebral cavernous malformation (CCM) Signaling complex (CSC) Progesterone (PRG) Mifepristone (MIF) Prognostic biomarkers Classic nuclear progesterone receptors (nPRs) |
| title | CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling |
| title_full | CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling |
| title_fullStr | CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling |
| title_full_unstemmed | CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling |
| title_short | CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling |
| title_sort | ccm signaling complex csc couples both classic and non classic progesterone receptor signaling |
| topic | Cerebral cavernous malformation (CCM) Signaling complex (CSC) Progesterone (PRG) Mifepristone (MIF) Prognostic biomarkers Classic nuclear progesterone receptors (nPRs) |
| url | https://doi.org/10.1186/s12964-022-00926-z |
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