Taken together, the preclinical study using in vivo mouse model confirms that targeting the newly identified ERβ/TGF‐β1/SMAD3 signals with the FDA‐approved anti‐estrogen ICI182,780 or the selective ERβ antagonist PHTPP could more effectively reduce RCC tumor growth and invasion. This evidence concerns the gene TGFB1 and renal cell carcinoma.