Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the
Gabriela Paroni1, Adriana Zanetti1, Maria Monica Barzago1
1Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, Italy.
Abstract:
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.
Insights
All-trans retinoic acid (ATRA) shows anti-tumor effects in triple-negative breast cancer (TNBC) cells with NOTCH1 activation. Combining ATRA with gamma-secretase inhibitors offers a promising therapeutic strategy for this TNBC subtype.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- Genetic aberrations in NOTCH1 signaling are observed in a subset of TNBC.
- All-trans retinoic acid (ATRA) has shown potential anti-proliferative effects.
Purpose of the Study:
- To investigate the sensitivity of TNBC cell lines to all-trans retinoic acid (ATRA).
- To explore the role of NOTCH1 activation in ATRA sensitivity.
- To evaluate combination therapies of ATRA with gamma-secretase inhibitors.
Main Methods:
- Profiling of 18 TNBC cell lines for ATRA sensitivity.
- Genetic analysis of NOTCH1 pathway components.
- In vitro and in vivo studies of ATRA and gamma-secretase inhibitor combinations (DAPT, PF-03084014).
- RNA-sequencing to analyze gene expression changes.
Main Results:
- Three TNBC cell lines (HCC-1599, MB-157, MDA-MB-157) sensitive to ATRA exhibited NOTCH1 genetic aberrations and constitutive N1ICD activation.
- N1ICD conferred sensitivity to both ATRA and gamma-secretase inhibitors.
- Combinations of ATRA and gamma-secretase inhibitors demonstrated additive/synergistic anti-tumor effects.
- ATRA inhibited cell growth via RARα, upregulating RARβ, a key mediator of its anti-proliferative activity.
Conclusions:
- ATRA exhibits significant anti-tumor activity specifically in TNBC cells with constitutive NOTCH1 activation.
- Combined ATRA and gamma-secretase inhibitor therapy is a viable strategy for treating this TNBC subtype.
- Results support the initiation of clinical trials for this targeted combination therapy.
More Related Videos
09:04Analysis of Retinoic Acid-induced Neural Differentiation of Mouse Embryonic Stem Cells in Two and Three-dimensional Embryoid Bodies
Published on: April 22, 2017
09:08Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
Related Concept Videos
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
01:23Negative Regulator Molecules
01:31Transducer Mechanism: Nuclear Receptors
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes: