Src is a novel potential off‐target of RXR agonists, 9‐cis‐UAB30 and Targretin, in human breast cancer cells

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 p70s6k, 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. © 2014 Wiley Periodicals, Inc.