Abstract 196: Lifetime and adulthood dietary genistein intake have opposing effect on tamoxifen resistance in rats.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC High childhood and adolescent dietary intake of isoflavone genistein (GEN) in soyfoods reduces later breast cancer risk, but since GEN has estrogenic properties, it is not clear whether it is safe to start consuming it after breast cancer has been diagnosed. Using a new preclinical model, we investigated the effects of childhood, adult and/or post-diagnosis consumption of GEN on the ability of tamoxifen (TAM) to treat breast cancer. 95 female Sprague-Dawley rats consuming AIN93G diet were supplemented with 0 or 500 ppm GEN between postnatal days (PND) 15 to 30 (prepubertal exposure) and then were fed AIN93G diet with no GEN between PND 30 and 55. On PND 48, rats received 10 mg DMBA to induce mammary tumors, and were then divided to four dietary groups on PND 55: prepubertal GEN-adult GEN group (GG, n=20); prepubertal GEN-adult control group (GC, n=20); prepubertal control-adult GEN (CG, n=20); and control-control (CC, n=35). When mammary tumor reached a size of 1.4 cm in diameter, 337 ppm TAM was added to rats’ diet. GG and CG rats continued also consuming GEN, and all rats in GC and 20 rats in CC groups stated consuming GEN one week after the TAM treatment started. 15 CC rats were never fed GEN. Mammary tumor latency was longer in GG (p<0.003) and GC rats (p<0.095), compared to CC rats. The response of tumors to TAM treatment was classified as complete or partial response, or de novo resistant. Prepubertal and life-time GEN intake increased, and intake starting during TAM treatment reduced response to TAM (p<0.001). Mammary cancer recurrence rate was highest in the rats which started consuming GEN during TAM treatment, and significantly lower in life-time, prepubertal and adulthood only GEN intake groups (p<0.001). Brca1 mRNA level was highest in the mammary gland of life-time GEN consuming rats (p<0.05). Tumor suppressor genes p21WAF1/CIP1 and p16INK4a mRNA levels were significantly higher in both prepubertal GEN groups (GC and GG) than in CC rats (p<0.05), as was the expression of pro-apoptotic gene Bax (p<0.05). No changes in estrogen receptor (ER) protein expression in the mammary gland were seen among the groups, but progesterone receptor (p<0.05) and phosphorylated HER2/ErbB2 (p<0.05) were both expressed at a lower level in rats consuming GEN through the life-time, compared with rats which consumed GEN during adult life (CG rats). Our findings show that rats exposed prepubertally or through the life-time to GEN were at lower risk of developing TAM resistance than rats which started GEN intake in adulthood or post-diagnosis. The effect of prepubertal GEN exposure in increasing TAM responsiveness may be related to up-regulation of tumor suppressor genes Brca1, p16INK4a and p21WAF1/CIP1 in their mammary gland. Recurrence rate was highest in those rats that were consuming GEN for the first time during TAM treatment. If true for humans, women with ER+ breast cancer should not start consuming GEN during TAM treatment. Citation Format: Xiyuan Zhang, Anni Warri, Idalia Cruz, Robert Clarke, Leena A. Hilakivi-Clarke. Lifetime and adulthood dietary genistein intake have opposing effect on tamoxifen resistance in rats. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 196. doi:10.1158/1538-7445.AM2013-196