All-trans retinoic acid modulates the plasticity and inhibits the motility of breast cancer cells: role of NOTCH1 and TGFβ
Abstract
All-trans retinoic acid (ATRA) is a natural compound proposed for the treatment/chemo-prevention 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 UACC-812 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/re-organisation of adherens and tight junctions.
Epithelial differentiation and augmented cell-cell contacts underlay the anti-migratory action exerted by the retinoid in cells exposed to the EMT-inducing factors, EGF and Heregulin-β1 (Herg).
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 Herg. 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 plays a role not only in the anti-migratory action of ATRA, but it is relevant also for the anti-proliferative activity of the retinoid in HCC-1599 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 DAPT supporting the concept that the two compounds act at the transcriptional and post-translational levels along the NOTCH1 pathway.
See also All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives).