9-cis-UAB30 (UAB30) and
Targretin are well-known
retinoid X receptor (RXR) agonists. They were highly effective in decreasing the incidence of
methylnitrosourea (MNU)-induced
mammary cancers. However, whether the anti-
mammary cancer effects of UAB30 or
Targretin originate from the activation of RXR is unclear. In the present study, we hypothesized that UAB30 and
Targretin not only affect RXR, but likely influence one or more off-target
proteins. Virtual screening results suggest that Src is a potential target for UAB30 and
Targretin that regulates extracellular matrix (ECM) molecules and cell motility and invasiveness. In vitro
kinase assay data revealed that UAB30 or
Targretin interacted with Src and attenuated its
kinase activity. We found that UAB30 or
Targretin substantially inhibited invasiveness and migration of MCF-7 and SK-BR-3 human
breast cancer cells. We examined the effects of UAB30 and
Targretin on the expression of
matrix metalloproteinases (MMP)-9, which are known to play an essential role in
tumor invasion. We show that activity and expression of MMP-9 were decreased by UAB30 or
Targretin. Western blot data showed that UAB30 or
Targretin decreased AKT and its substrate molecule p70(s6k), which are downstream of Src in MCF-7 and SK-BR-3 cells. Moreover, knocking down the expression of Src effectively reduced the sensitivity of SK-BR-3 cells to the inhibitory effects of UAB30 and
Targretin on invasiveness. Taken together, our results demonstrate that UAB30 and
Targretin each inhibit invasion and migration by targeting Src in human
breast cancer cells.