All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells
All-trans retinoic acid (ATRA), a recognized differentiating agent, has significant potential in the personalized/stratified treatment of breast cancer. The present study reports on the molecular mechanisms underlying the anti-tumor activity of ATRA in breast cancer. The work is based on transcripto...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/5/1169 |
| _version_ | 1797568778795483136 |
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| author | Marco Bolis Gabriela Paroni Maddalena Fratelli Arianna Vallerga Luca Guarrera Adriana Zanetti Mami Kurosaki Silvio Ken Garattini Maurizio Gianni’ Monica Lupi Linda Pattini Maria Monica Barzago Mineko Terao Enrico Garattini |
| author_facet | Marco Bolis Gabriela Paroni Maddalena Fratelli Arianna Vallerga Luca Guarrera Adriana Zanetti Mami Kurosaki Silvio Ken Garattini Maurizio Gianni’ Monica Lupi Linda Pattini Maria Monica Barzago Mineko Terao Enrico Garattini |
| author_sort | Marco Bolis |
| collection | DOAJ |
| description | All-trans retinoic acid (ATRA), a recognized differentiating agent, has significant potential in the personalized/stratified treatment of breast cancer. The present study reports on the molecular mechanisms underlying the anti-tumor activity of ATRA in breast cancer. The work is based on transcriptomic experiments performed on ATRA-treated breast cancer cell-lines, short-term tissue cultures of patient-derived mammary-tumors and a xenograft model. ATRA upregulates gene networks involved in interferon-responses, immune-modulation and antigen-presentation in retinoid-sensitive cells and tumors characterized by poor immunogenicity. ATRA-dependent upregulation of these gene networks is caused by a viral mimicry process, involving the activation of endogenous retroviruses. ATRA induces a non-canonical type of viral mimicry, which results in increased expression of the <i>IRF1</i> (Interferon Responsive Factor 1) transcription factor and the DTX3L (Deltex-E3-Ubiquitin-Ligase-3L) downstream effector. Functional knockdown studies indicate that <i>IRF1</i> and <i>DTX3L</i> are part of a negative feedback loop controlling ATRA-dependent growth inhibition of breast cancer cells. The study is of relevance from a clinical/therapeutic perspective. In fact, ATRA stimulates processes controlling the sensitivity to immuno-modulatory drugs, such as immune-checkpoint-inhibitors. This suggests that ATRA and immunotherapeutic agents represent rational combinations for the personalized treatment of breast cancer. Remarkably, ATRA-sensitivity seems to be relatively high in immune-cold mammary tumors, which are generally resistant to immunotherapy. |
| first_indexed | 2024-03-10T20:00:48Z |
| format | Article |
| id | doaj.art-e389d39afd9d4fcb887ee5cc3591bae2 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:00:48Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e389d39afd9d4fcb887ee5cc3591bae22023-11-19T23:35:18ZengMDPI AGCancers2072-66942020-05-01125116910.3390/cancers12051169All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer CellsMarco Bolis0Gabriela Paroni1Maddalena Fratelli2Arianna Vallerga3Luca Guarrera4Adriana Zanetti5Mami Kurosaki6Silvio Ken Garattini7Maurizio Gianni’8Monica Lupi9Linda Pattini10Maria Monica Barzago11Mineko Terao12Enrico Garattini13Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyDepartment of Oncology, Azienda Ospedaliera di Udine, DAME, Dipartimento di Area Medica Università degli Studi di Udine, 33100 Udine, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyDepartment of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via La Masa 19, 20156 Milano, ItalyDepartment of Electronics, Information and Bioengineering, Politecnico di Milano, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyLaboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, ItalyAll-trans retinoic acid (ATRA), a recognized differentiating agent, has significant potential in the personalized/stratified treatment of breast cancer. The present study reports on the molecular mechanisms underlying the anti-tumor activity of ATRA in breast cancer. The work is based on transcriptomic experiments performed on ATRA-treated breast cancer cell-lines, short-term tissue cultures of patient-derived mammary-tumors and a xenograft model. ATRA upregulates gene networks involved in interferon-responses, immune-modulation and antigen-presentation in retinoid-sensitive cells and tumors characterized by poor immunogenicity. ATRA-dependent upregulation of these gene networks is caused by a viral mimicry process, involving the activation of endogenous retroviruses. ATRA induces a non-canonical type of viral mimicry, which results in increased expression of the <i>IRF1</i> (Interferon Responsive Factor 1) transcription factor and the DTX3L (Deltex-E3-Ubiquitin-Ligase-3L) downstream effector. Functional knockdown studies indicate that <i>IRF1</i> and <i>DTX3L</i> are part of a negative feedback loop controlling ATRA-dependent growth inhibition of breast cancer cells. The study is of relevance from a clinical/therapeutic perspective. In fact, ATRA stimulates processes controlling the sensitivity to immuno-modulatory drugs, such as immune-checkpoint-inhibitors. This suggests that ATRA and immunotherapeutic agents represent rational combinations for the personalized treatment of breast cancer. Remarkably, ATRA-sensitivity seems to be relatively high in immune-cold mammary tumors, which are generally resistant to immunotherapy.https://www.mdpi.com/2072-6694/12/5/1169breast cancerretinoic acidantigen presentationinterferonimmune response |
| spellingShingle | Marco Bolis Gabriela Paroni Maddalena Fratelli Arianna Vallerga Luca Guarrera Adriana Zanetti Mami Kurosaki Silvio Ken Garattini Maurizio Gianni’ Monica Lupi Linda Pattini Maria Monica Barzago Mineko Terao Enrico Garattini All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells Cancers breast cancer retinoic acid antigen presentation interferon immune response |
| title | All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells |
| title_full | All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells |
| title_fullStr | All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells |
| title_full_unstemmed | All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells |
| title_short | All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells |
| title_sort | all trans retinoic acid stimulates viral mimicry interferon responses and antigen presentation in breast cancer cells |
| topic | breast cancer retinoic acid antigen presentation interferon immune response |
| url | https://www.mdpi.com/2072-6694/12/5/1169 |
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