Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition
Abstract Background Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-02-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-021-01401-2 |
| _version_ | 1818325651380240384 |
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| author | Jun Tian Vivian Wang Ni Wang Baharak Khadang Julien Boudreault Khldoun Bakdounes Suhad Ali Jean-Jacques Lebrun |
| author_facet | Jun Tian Vivian Wang Ni Wang Baharak Khadang Julien Boudreault Khldoun Bakdounes Suhad Ali Jean-Jacques Lebrun |
| author_sort | Jun Tian |
| collection | DOAJ |
| description | Abstract Background Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors. Methods By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC. Results We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo. Conclusions Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment. |
| first_indexed | 2024-12-13T11:47:52Z |
| format | Article |
| id | doaj.art-d805fa68594c4a45a5c184ed6191e865 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-13T11:47:52Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-d805fa68594c4a45a5c184ed6191e8652022-12-21T23:47:28ZengBMCBreast Cancer Research1465-542X2021-02-0123111810.1186/s13058-021-01401-2Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibitionJun Tian0Vivian Wang1Ni Wang2Baharak Khadang3Julien Boudreault4Khldoun Bakdounes5Suhad Ali6Jean-Jacques Lebrun7Department of Medicine, McGill University Health Center, Cancer Research ProgramDepartment of Medicine, McGill University Health Center, Cancer Research ProgramDepartment of Medicine, McGill University Health Center, Cancer Research ProgramDepartment of Medicine, McGill University Health Center, Cancer Research ProgramDepartment of Medicine, McGill University Health Center, Cancer Research ProgramDepartment of Medicine, McGill University Health Center, Cancer Research ProgramDepartment of Medicine, McGill University Health Center, Cancer Research ProgramDepartment of Medicine, McGill University Health Center, Cancer Research ProgramAbstract Background Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors. Methods By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC. Results We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo. Conclusions Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment.https://doi.org/10.1186/s13058-021-01401-2COX-2CelecoxibBreast cancerTNBCDrug resistanceMGFE8 |
| spellingShingle | Jun Tian Vivian Wang Ni Wang Baharak Khadang Julien Boudreault Khldoun Bakdounes Suhad Ali Jean-Jacques Lebrun Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition Breast Cancer Research COX-2 Celecoxib Breast cancer TNBC Drug resistance MGFE8 |
| title | Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition |
| title_full | Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition |
| title_fullStr | Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition |
| title_full_unstemmed | Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition |
| title_short | Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition |
| title_sort | identification of mfge8 and klk5 7 as mediators of breast tumorigenesis and resistance to cox 2 inhibition |
| topic | COX-2 Celecoxib Breast cancer TNBC Drug resistance MGFE8 |
| url | https://doi.org/10.1186/s13058-021-01401-2 |
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