A Snapshot of the Molecular Biology of Notch Signaling: Challenges and Promises

Reichrath, Jörg; Reichrath, Sandra

doi:10.1007/978-3-030-36422-9_1

Cited by 7 publications

(1 citation statement)

References 19 publications

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“…NOTCH1 is a transmembrane receptor and its constitutive activation is observed in approximately 3% of all TNBC cases [ 3 , 4 ]. Normally, NOTCH1 activation requires binding to a membrane tethered ligand on neighboring cells, which triggers a series of proteolytic events [ 5 , 6 ]. The final γ-secretase-dependent cleavage of NOTCH1 causes the release and nuclear translocation of the receptor intracellular domain (N1ICD), which is part of an active transcriptional complex controlling the expression of various target genes [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ

Paroni

Zanetti

Barzago

et al. 2020

Cancers

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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.

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