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 2020-10-18 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. application/pdf https://n2t.net/ark:/12658/srd1319349 https://susi.usi.ch/global/documents/319349 https://susi.usi.ch/documents/319349/files/Bolis_2020_MDPI_cancers.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.3390/cancers12103027 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319349 info:eu-repo/semantics/openAccess CC BY Cancers. - 2020, vol. 12, no. 10, p. 23 p Retinoic acid Breast cancer Triple-negative Notch1 RARbeta info:eu-repo/classification/udc/61 Retinoic acid sensitivity of triple-negative breast cancer cells characterized by constitutive activation of the NOTCH1 pathway : the role of RARβ http://purl.org/coar/resource_type/c_6501