Retinoic acid sensitivity of triple-negative breast cancer cells characterized by constitutive activation of the NOTCH1 pathway

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

doi:10.3390/cancers12103027

Back

Journal article

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

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