Retinoic acid sensitivity of triple-negative breast cancer cells characterized by constitutive activation of the NOTCH1 pathway : the role of RARβ
- Paroni, Gabriela Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Zanetti, Adriana Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Barzago, Maria Monica Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Kurosaki, Mami Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Guarrera, Luca Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Fratelli, Maddalena Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Troiani, Martina Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Ubezio, Paolo Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Bolis, Marco Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy - Functional Cancer Genomics Laboratory, Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
- Vallerga, Arianna Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Biancardi, Federica Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Terao, Mineko Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
- Garattini, Enrico Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
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18.10.2020
Published in:
- Cancers. - 2020, vol. 12, no. 10, p. 23 p
English
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.
- Language
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- English
- Classification
- Medicine
- License
- CC BY
- Open access status
- gold
- Identifiers
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- RERO DOC 330314
- DOI 10.3390/cancers12103027
- ARK ark:/12658/srd1319349
- Persistent URL
- https://n2t.net/ark:/12658/srd1319349
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