Abstract 1613: Dietary isoflavone decreases prostate cancer progression and improves survival in conditionalPten/Trp53-deficient mice

Abstract

Epidemiological data has shown that dietary practices can greatly influence cancer rates. Men in East Asian countries, men have significantly lower prostate cancer rates compared to their counterparts the US and Europe. Soybeans are a versatile and rich source of protein and its products constitute a rich portion of Asian diets. Recent interest in healthy eating has expanded the consumption of soy products which also provide a rich source of naturally occurring isoflavones and 17β-estradiol. In this study, we used roasted soybean flour (kinako), which contains high levels isoflavones glycosides and estradiol, as dietary soy source to determine the influence of isoflavones rich diets on prostate cancer. Six-week old conditional Pten/Trp53 double knockout mice were randomized and fed plain AIN-93M (Control) diets or a diets supplemented with kinako ad libitum. Concentrations of kinako were adjusted to for daily intakes of aglycone isoflavones (genistein, daidzein, and glycetein) of 400 (LDI) and 800 (HDI) mg. Mice were sacrificed at 16 and 20 weeks (n=6 mice/group) or maintained for survival assessment (n=8 mice/group). Dietary intake of kinako-supplemented diets did not influence the onset of prostatic intraepithelial neoplasia or tumor burden at the early stages. However, tumors from mice fed the HDI diet experienced reduced tumor proliferation rates. Moreover, mice fed LDI and HDI diets showed reduced androgen receptor (AR) protein expression levels as well as mRNA levels for the AR target genes Fkbp5, Nk3x3.1 and Timp4. Interestingly, mice on the LDI diet, but not the HDI, experienced longer times to disease progression (median times 264, 299 and 250 days for Control, LDI and HDI, respectively, P=0.663), tumor doubling (median times 14, 27 and 14 days for Control, LDI and HDI, respectively, P=0.083), cumulative survival (median times 292, 348 and 320 days for Control, LDI and HDI, respectively, P=0.199), and overall survival times (median times 28, 43 and 35 days for Control, LDI and HDI, respectively, P=0.324). The metastatic incidence was 33%, 14% and 14% for Control, LDI and HDI groups, respectively, P=0.631. We also investigated whether dietary intervention with kinako would impact previously stablished tumors. For this we fed kinako supplemented diets to conditional Pten-knockout mice with established tumors but no changes were observed in tumor burden, proliferation, apoptosis and AR activity. Together our data shows that long-term continuous ingestion of a diet rich in isoflavones may be necessary in order suppress tumor growth. Interestingly, this protective effect appears to be lost with high-doses of the dietary isoflavones. Further studies will need to be performed in order to decipher complex dynamic interplay between survival pathways isoflavones chemoprevention. Citation Format: Yasunori Mori, Marco A. De Velasco, Yurie Kura, Eri Banno, Naomi Ando, Noriko Sato, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuko Sakai, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Dietary isoflavone decreases prostate cancer progression and improves survival in conditional Pten/Trp53-deficient mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1613.