Abstract
We have previously observed that life‐time dietary intake of genistein (GEN) prevents development of tamoxifen (TAM) resistance in rat mammary tumor. This study investigated the mechanisms explaining this effect.Female Sprague‐Dawley rats were supplemented with 0 or 500 ppm GEN before puberty. Mammary carcinogen DMBA was administered at 48 days of age, and four dietary groups were established: lifelong GEN, prepubertal GEN, adult GEN and controls. Rats were then treated with 337 ppm TAM citrate via diet, and those fed GEN lifelong or during adult life were kept on GEN during TAM treatment. GEN was also given again to the rats consuming it at prepuberty and to some control rats. The remaining TAM treated control rats were never fed GEN. Tumors of rats fed GEN during prepuberty or lifelong exhibited reduced resistance to TAM, compared to no GEN controls, whilst adult only GEN intake caused TAM resistance (p<0.001). Mammary cancer recurrence rate was highest in the rats which started consuming GEN during TAM treatment (p<0.001).Chronic activation of the unfolded protein response (UPR) pathway has been linked to TAM resistance. We found that the active form of ATF6, ATF6 p50, was higher in normal mammary glands of lifelong GEN fed rats than in the controls (p<0.05). mRNA expression of its target genes, Xbp1 and GRP78, were also higher in the lifelong GEN group (p<0.05). However, the levels of GRP78, IRE1α, ATF4 and Beclin were significantly lower in the tumors of lifelong GEN exposed rats compared with adulthood only GEN fed rats (p<0.05).Thus, lifelong GEN intake may stimulate responsiveness of mammary tumors to TAM by affecting the UPR pathway:members of this pathway were activated in the normal mammary gland and suppressed in the tumors of lifelong GEN consuming rats. Mammary tumor response to TAM treatment no GEN control post‐diagnosis GEN adult GEN prepubertal GEN lifelong GEN Complete response (%) 54 33 38 56 52 Partial response (%) 8 16 21 21 24 Resistance (%) 38 51 41 23 24 Recurrence (% of complete response) 23 33 7 11 18 Grant Funding Source: Supported by NCI U54CA149147
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