NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression
Abstract Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor...
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| Format: | Article |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54651-x |
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| author | Tejaswini Reddy Akshjot Puri Liliana Guzman-Rojas Christoforos Thomas Wei Qian Jianying Zhou Hong Zhao Bijan Mahboubi Adrian Oo Young-Jae Cho Baek Kim Jose Thaiparambil Roberto Rosato Karina Ortega Martinez Maria Florencia Chervo Camila Ayerbe Noah Giese David Wink Stephen Lockett Stephen Wong Jeffrey Chang Savitri Krishnamurthy Clinton Yam Stacy Moulder Helen Piwnica-Worms Funda Meric-Bernstam Jenny Chang |
| author_facet | Tejaswini Reddy Akshjot Puri Liliana Guzman-Rojas Christoforos Thomas Wei Qian Jianying Zhou Hong Zhao Bijan Mahboubi Adrian Oo Young-Jae Cho Baek Kim Jose Thaiparambil Roberto Rosato Karina Ortega Martinez Maria Florencia Chervo Camila Ayerbe Noah Giese David Wink Stephen Lockett Stephen Wong Jeffrey Chang Savitri Krishnamurthy Clinton Yam Stacy Moulder Helen Piwnica-Worms Funda Meric-Bernstam Jenny Chang |
| author_sort | Tejaswini Reddy |
| collection | DOAJ |
| description | Abstract Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH2-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC. |
| format | Article |
| id | doaj-art-6febbe39f2114567b607ed81238dfeec |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6febbe39f2114567b607ed81238dfeec2025-01-05T12:35:29ZengNature PortfolioNature Communications2041-17232024-12-0115111810.1038/s41467-024-54651-xNOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repressionTejaswini Reddy0Akshjot Puri1Liliana Guzman-Rojas2Christoforos Thomas3Wei Qian4Jianying Zhou5Hong Zhao6Bijan Mahboubi7Adrian Oo8Young-Jae Cho9Baek Kim10Jose Thaiparambil11Roberto Rosato12Karina Ortega Martinez13Maria Florencia Chervo14Camila Ayerbe15Noah Giese16David Wink17Stephen Lockett18Stephen Wong19Jeffrey Chang20Savitri Krishnamurthy21Clinton Yam22Stacy Moulder23Helen Piwnica-Worms24Funda Meric-Bernstam25Jenny Chang26Department of Internal Medicine, Baylor College of MedicineHouston Methodist Research InstituteHouston Methodist Research InstituteHouston Methodist Research InstituteHouston Methodist Research InstituteHouston Methodist Research InstituteHouston Methodist Research InstituteAdams School of Dentistry, University of North CarolinaDepartment of Pediatrics, School of Medicine, Emory UniversityDepartment of Pediatrics, School of Medicine, Emory UniversityDepartment of Pediatrics, School of Medicine, Emory UniversityHouston Methodist Research InstituteHouston Methodist Research InstituteHouston Methodist Research InstituteHouston Methodist Research InstituteMcGovern Medical School, The University of Texas Health Science CenterHouston Methodist Research InstituteCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of HealthOptical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of HealthHouston Methodist Research InstituteMcGovern Medical School, The University of Texas Health Science CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterEli Lilly and CompanyThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterHouston Methodist Research InstituteAbstract Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH2-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC.https://doi.org/10.1038/s41467-024-54651-x |
| spellingShingle | Tejaswini Reddy Akshjot Puri Liliana Guzman-Rojas Christoforos Thomas Wei Qian Jianying Zhou Hong Zhao Bijan Mahboubi Adrian Oo Young-Jae Cho Baek Kim Jose Thaiparambil Roberto Rosato Karina Ortega Martinez Maria Florencia Chervo Camila Ayerbe Noah Giese David Wink Stephen Lockett Stephen Wong Jeffrey Chang Savitri Krishnamurthy Clinton Yam Stacy Moulder Helen Piwnica-Worms Funda Meric-Bernstam Jenny Chang NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression Nature Communications |
| title | NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression |
| title_full | NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression |
| title_fullStr | NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression |
| title_full_unstemmed | NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression |
| title_short | NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression |
| title_sort | nos inhibition sensitizes metaplastic breast cancer to pi3k inhibition and taxane therapy via c jun repression |
| url | https://doi.org/10.1038/s41467-024-54651-x |
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