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It has been demonstrated that the chemopreventive agentN-(4-hydroxyphenyl)retinamide (4-HPR) induces apoptotic cell death, but recent data has suggested that late stage/recurrent tumours lose their response to 4-HPR-induced cell death by mechanisms that are unknown. Our study investigated the ability of 4-HPR to induce cell death in keratinocyte cell lines that represent different stages of carcinogenesis and the role of TGF-β signalling in the induction of cell death by 4-HPR. We show that treatment of the immortalised keratinocyte cell line HaCaT with 10−5 M 4-HPR induced cell death by apoptosis and caused an accumulation of cells in the G0/G1 phase of the cell cycle. Using a genetically related series of human skin keratinocytes derived from HaCaT that reflect tumour progression and metastasisin vivo, we demonstrate that 4-HPR-induced cell death and apoptosis is attenuated in the more aggressive tumour cell lines but that a reduced level of response is retained. Response to TGF-β-induced growth inhibition was also reduced in the more aggressive cell lines. Treatment of HaCaT cells with 4-HPR induced TGF-β2 expression and an increase in the amount of active TGF-β in the culture medium. The inhibition of TGF-β signalling attenuated 4-HPR-induced apoptosis and both TGF-β1 and TGF-β2 potentiated 4-HPR-induced apoptosis and enhanced 4-HPR-induced growth inhibition. Our results demonstrate that loss of response to 4-HPR correlates with a loss of response to the growth inhibitory effects of TGF-β and that adjuvant therapies that upregulate TGF-β may enhance the chemopreventive effects of 4-HPR.