The present invention resides in the discovery that Smad3, a key downstream mediator of TGF-β signaling, plays a critical role in development and progression of cancer. Thus, this application provides for a novel method of treating cancer by inhibiting Smad3 signaling, such as through administration of SIS3, an inhibitor of Smad3. Further provided are compositions and kits useful for treating cancer by way of inhibiting Smad3 signaling.