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Open AccessArticle

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

1
Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, Italy
2
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156 Milano, Italy
3
Functional Cancer Genomics Laboratory, Institute of Oncology Research, USI, University of Southern Switzerland, 6500 Bellinzona, Switzerland
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 3027; https://doi.org/10.3390/cancers12103027
Received: 21 September 2020 / Revised: 13 October 2020 / Accepted: 15 October 2020 / Published: 18 October 2020
(This article belongs to the Section Molecular Cancer Biology)
We provide experimental evidence that the rare subgroup of triple-negative breast cancer characterized by constitutive activation of the NOTCH1 signaling pathway is sensitive to the anti-tumor action of all-trans retinoic acid, the active metabolite of vitamin A. In this tumor context, all-trans retinoic acid exerts not only an effective action on its own, but it also stimulates the inhibitory activity of γ-secretase inhibitors, a series of therapeutic agents targeting NOTCH1, on cancer cell growth. From a basic and mechanistic standpoint, an important result of the study regards the specific involvement of the retinoid receptor RARβ in the anti-tumor action exerted by all-trans retinoic acid in sensitive triple-negative breast cancer cells. From an applicative point of view the study represents the basis for the design of clinical trials on the efficacy of combinations between all-trans retinoic acid and γ-secretase inhibitors in the treatment of patients affected by a specific subtype of triple-negative breast cancer.
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. View Full-Text
Keywords: retinoic acid; breast cancer; triple-negative; Notch1; RARbeta retinoic acid; breast cancer; triple-negative; Notch1; RARbeta
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Paroni, G.; Zanetti, A.; Barzago, M.M.; Kurosaki, M.; Guarrera, L.; Fratelli, M.; Troiani, M.; Ubezio, P.; Bolis, M.; Vallerga, A.; Biancardi, F.; Terao, M.; Garattini, E. Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ. Cancers 2020, 12, 3027.

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