Abstract LB-167: Prepubertal or lifetime genistein intake reduces risk of tamoxifen resistance in rats

Abstract

Abstract Using a preclinical model, we studied whether consumption of soy isoflavone genistein (GEN) during childhood modifies the effect of adult GEN intake on the ability of tamoxifen (TAM) to inhibit mammary tumor growth. Female rats were fed AIN93G control diet supplemented with 0 or 500 ppm genistein between postnatal days (PND) 15 and 30 (prepubertal exposure); on PND30 both groups received control diet. They were then exposed on PND50 to DMBA, and on PND57 divided to four dietary groups (n=20-40 per group) (see Table). Most rats in all four groups developed mammary tumors, but tumor latency was longer in the prepubertally GEN fed G-G (P<0.003) and G-C groups (p<0.095), compared to controls. TAM treatment (338 ppm in the diet) was started when tumor reached a size of 1.4 cm, and rats were followed for 18 weeks. The response to TAM was determined as complete response (CR), partial response (PR), or as being resistant. Adding GEN to the diet when TAM treatment started increased TAM resistance by 48%, compared to rats which were never fed GEN. Adult GEN intake (C-G group) further reduced CR. However, protein levels in the tumors of genes involved in unfolded-protein response and associated with TAM resistance (IRE1a, BIP, ATF4, BECLIN1, CHOP, ER), were not affected. Prepubertal GEN intake in G-C and G-G groups significantly increased the rate of CR and inhibited TAM resistance. Total tumor burden, which reflects the response of all tumors per rat to TAM, including those appearing during TAM treatment (de novo TAM resistant) was significantly higher in the rats which received GEN as adults, compared to the other three groups (p<0.001); lowest tumor burden was seen in the rats which consumed GEN both during prepuberty and as adults. Our findings suggest that prepubertally GEN fed rats, also when they continue to consume GEN in adulthood, are at low risk of developing TAM resistance. In contrast, adult only GEN consumption significantly impaired response to TAM. Mechanisms explaining these data are currently being investigated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-167. doi:1538-7445.AM2012-LB-167