Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ
Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks effective therapeutic options. In this study, we profile eighteen TNBC cell lines for their sensitivity to the anti-proliferative action of all-trans retinoic acid (ATRA). The only three cell lines (HCC-1599, MB-157 and MDA-M...
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| Veröffentlicht in: | Cancers 2020-10, Vol.12 (10), p.3027 |
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| creator | Paroni, Gabriela Zanetti, Adriana Barzago, Maria Monica Kurosaki, Mami Guarrera, Luca Fratelli, Maddalena Troiani, Martina Ubezio, Paolo Bolis, Marco Vallerga, Arianna Biancardi, Federica Terao, Mineko Garattini, Enrico |
| description | Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks effective therapeutic options. In this study, we profile eighteen TNBC cell lines for their sensitivity to the anti-proliferative action of all-trans retinoic acid (ATRA). The only three cell lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by genetic aberrations of the NOTCH1-gene, causing constitutive activation of the NOTCH1 γ-secretase product, N1ICD. N1ICD renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors (DAPT; PF-03084014). Combinations of ATRA and γ-secretase inhibitors produce additive/synergistic effects in vitro and in vivo. RNA-sequencing studies of HCC-1599 and MB-157 cells exposed to ATRA and DAPT and ATRA+DAPT demonstrate that the two compounds act on common gene sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. RARβ is a key determinant of ATRA anti-proliferative activity, as its silencing suppresses the effects exerted by the retinoid. In conclusion, we demonstrate that ATRA exerts a significant anti-tumor action only in TNBC cells showing constitutive NOTCH1 activation. Our results support the design of clinical trials involving combinations between ATRA and γ-secretase inhibitors for the treatment of this TNBC subtype. |
| doi_str_mv | 10.3390/cancers12103027 |
| format | Article |
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In this study, we profile eighteen TNBC cell lines for their sensitivity to the anti-proliferative action of all-trans retinoic acid (ATRA). The only three cell lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by genetic aberrations of the NOTCH1-gene, causing constitutive activation of the NOTCH1 γ-secretase product, N1ICD. N1ICD renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors (DAPT; PF-03084014). Combinations of ATRA and γ-secretase inhibitors produce additive/synergistic effects in vitro and in vivo. RNA-sequencing studies of HCC-1599 and MB-157 cells exposed to ATRA and DAPT and ATRA+DAPT demonstrate that the two compounds act on common gene sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. RARβ is a key determinant of ATRA anti-proliferative activity, as its silencing suppresses the effects exerted by the retinoid. In conclusion, we demonstrate that ATRA exerts a significant anti-tumor action only in TNBC cells showing constitutive NOTCH1 activation. Our results support the design of clinical trials involving combinations between ATRA and γ-secretase inhibitors for the treatment of this TNBC subtype.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12103027</identifier><identifier>PMID: 33081033</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Breast cancer ; Cell activation ; Clinical trials ; DNA methylation ; Gene expression ; Leukemia ; Ligands ; Notch1 protein ; Retinoic acid ; Secretase ; Signal transduction ; Tumors ; Vitamin A</subject><ispartof>Cancers, 2020-10, Vol.12 (10), p.3027</ispartof><rights>2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 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In this study, we profile eighteen TNBC cell lines for their sensitivity to the anti-proliferative action of all-trans retinoic acid (ATRA). The only three cell lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by genetic aberrations of the NOTCH1-gene, causing constitutive activation of the NOTCH1 γ-secretase product, N1ICD. N1ICD renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors (DAPT; PF-03084014). Combinations of ATRA and γ-secretase inhibitors produce additive/synergistic effects in vitro and in vivo. RNA-sequencing studies of HCC-1599 and MB-157 cells exposed to ATRA and DAPT and ATRA+DAPT demonstrate that the two compounds act on common gene sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. 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Our results support the design of clinical trials involving combinations between ATRA and γ-secretase inhibitors for the treatment of this TNBC subtype.</description><subject>Breast cancer</subject><subject>Cell activation</subject><subject>Clinical trials</subject><subject>DNA methylation</subject><subject>Gene expression</subject><subject>Leukemia</subject><subject>Ligands</subject><subject>Notch1 protein</subject><subject>Retinoic acid</subject><subject>Secretase</subject><subject>Signal transduction</subject><subject>Tumors</subject><subject>Vitamin A</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1u1DAQxy0EotXSM1dLXLiE-iOJYw5IS8SXVAFalrPlOOPGVdZebKdoeQwehQfhmfC2FYL6MtbM__-zZwahp5S84FySc6O9gZgoo4QTJh6gU0YEq9pW1g__uZ-gs5SuSDmcU9GKx-iEc9IVEz9FPzeQnQ_O4LVxI_4CPrnsrl0-4GDxNrr9DNVHuNQlCfh1BJ0y7m8exj3Mc8L9pKM2GaL7ASMeDrgPPmWXlxvH2pRQzMEfeXkC7EM2E8WfdZ6-68NLvC25TZjhWN_o-PvXE_TI6jnB2V1coa9v32z799XFp3cf-vVFZbjscmU74IJoaoVsGe0621hpQLCBNdZyUgumGyOobEZC6NhIPVo5jFQOYAQxkvAVenXL3S_DDkYDPkc9q310Ox0PKmin_q94N6nLcK1E2xDR8AJ4fgeI4dsCKaudS6YMRXsIS1Ksbpjsas6P0mf3pFdhib60p1hTi5Z1dSGu0PmtysSQUgT79zOUqOPK1b2V8z9pYqFk</recordid><startdate>20201018</startdate><enddate>20201018</enddate><creator>Paroni, Gabriela</creator><creator>Zanetti, Adriana</creator><creator>Barzago, Maria Monica</creator><creator>Kurosaki, Mami</creator><creator>Guarrera, Luca</creator><creator>Fratelli, Maddalena</creator><creator>Troiani, Martina</creator><creator>Ubezio, Paolo</creator><creator>Bolis, Marco</creator><creator>Vallerga, Arianna</creator><creator>Biancardi, Federica</creator><creator>Terao, Mineko</creator><creator>Garattini, Enrico</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8231-713X</orcidid><orcidid>https://orcid.org/0000-0001-7475-3345</orcidid><orcidid>https://orcid.org/0000-0002-5825-9707</orcidid><orcidid>https://orcid.org/0000-0001-8983-886X</orcidid><orcidid>https://orcid.org/0000-0003-0412-9891</orcidid><orcidid>https://orcid.org/0000-0002-9976-9869</orcidid><orcidid>https://orcid.org/0000-0002-1769-3427</orcidid></search><sort><creationdate>20201018</creationdate><title>Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ</title><author>Paroni, Gabriela ; 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In this study, we profile eighteen TNBC cell lines for their sensitivity to the anti-proliferative action of all-trans retinoic acid (ATRA). The only three cell lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by genetic aberrations of the NOTCH1-gene, causing constitutive activation of the NOTCH1 γ-secretase product, N1ICD. N1ICD renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors (DAPT; PF-03084014). Combinations of ATRA and γ-secretase inhibitors produce additive/synergistic effects in vitro and in vivo. RNA-sequencing studies of HCC-1599 and MB-157 cells exposed to ATRA and DAPT and ATRA+DAPT demonstrate that the two compounds act on common gene sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. RARβ is a key determinant of ATRA anti-proliferative activity, as its silencing suppresses the effects exerted by the retinoid. In conclusion, we demonstrate that ATRA exerts a significant anti-tumor action only in TNBC cells showing constitutive NOTCH1 activation. Our results support the design of clinical trials involving combinations between ATRA and γ-secretase inhibitors for the treatment of this TNBC subtype.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>33081033</pmid><doi>10.3390/cancers12103027</doi><orcidid>https://orcid.org/0000-0001-8231-713X</orcidid><orcidid>https://orcid.org/0000-0001-7475-3345</orcidid><orcidid>https://orcid.org/0000-0002-5825-9707</orcidid><orcidid>https://orcid.org/0000-0001-8983-886X</orcidid><orcidid>https://orcid.org/0000-0003-0412-9891</orcidid><orcidid>https://orcid.org/0000-0002-9976-9869</orcidid><orcidid>https://orcid.org/0000-0002-1769-3427</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central; EZB Electronic Journals Library; PubMed Central Open Access |
| subjects | Breast cancer Cell activation Clinical trials DNA methylation Gene expression Leukemia Ligands Notch1 protein Retinoic acid Secretase Signal transduction Tumors Vitamin A |
| title | Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ |
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