title: All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells: ROLE OF NOTCH1 AND TRANSFORMING GROWTH FACTOR (TGFβ).
abstract: All-trans-retinoic acid (ATRA) is a natural compound proposed for the treatment/chemoprevention of breast cancer. Increasing evidence indicates that aberrant regulation of epithelial-to-mesenchymal transition (EMT) is a determinant of the cancer cell invasive and metastatic behavior. The effects of ATRA on EMT are largely unknown. In HER2-positive SKBR3 and UACC812 cells, showing co-amplification of the ERBB2 and RARA genes, ATRA activates a RARα-dependent epithelial differentiation program. In SKBR3 cells, this causes the formation/reorganization of adherens and tight junctions. Epithelial differentiation and augmented cell-cell contacts underlie the anti-migratory action exerted by the retinoid in cells exposed to the EMT-inducing factors EGF and heregulin-β1. Down-regulation of NOTCH1, an emerging EMT modulator, is involved in the inhibition of motility by ATRA. Indeed, the retinoid blocks NOTCH1 up-regulation by EGF and/or heregulin-β1. Pharmacological inhibition of γ-secretase and NOTCH1 processing also abrogates SKBR3 cell migration. Stimulation of TGFβ contributes to the anti-migratory effect of ATRA. The retinoid switches TGFβ from an EMT-inducing and pro-migratory determinant to an anti-migratory mediator. Inhibition of the NOTCH1 pathway not only plays a role in the anti-migratory action of ATRA; it is relevant also for the anti-proliferative activity of the retinoid in HCC1599 breast cancer cells, which are addicted to NOTCH1 for growth/viability. This effect is enhanced by the combination of ATRA and the γ-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-l-alanyl)-S-phenylglycine t-butyl ester, supporting the concept that the two compounds act at the transcriptional and post-translational levels along the NOTCH1 pathway.
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zanetti
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Affatato
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Centritto
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Mami
authors.initials: M
authors.lastname: Kurosaki
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Maria Monica
authors.initials: MM
authors.lastname: Barzago
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bolis
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Mineko
authors.initials: M
authors.lastname: Terao
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy. Electronic address: gabriela.paroni@marionegri.it.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Paroni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D051881:Receptor, Notch1 / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C000607071:RARA protein, human; D051881:Receptor, Notch1; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014212:Tretinoin
keywords: NOTCH pathway; cancer biology; cancer therapy; cell biology; cell differentiation; cell migration; epithelial-mesenchymal transition (EMT); nuclear receptor; retinoic acid; retinoid