Abstract P4-09-03: A diet enriched by soy-derived isoflavones impacts on the development of premalignant stages of breast cancer in an estrogen driven carcinogenesis animal model
Authors: Moeller FJ , Raffaelli F , Zierau O , Muders M , Soukup S , Kulling S , Vollmer G 
Published: August 2014

Abstract
Background: Hundred thousands of mainly postmenopausal women are using dietary supplements enriched with soy-derived isoflavones (sISO), such as the Novasoy® extract, to relief from climacteric complaints. At the same time, hundreds of studies controversially discuss the impact of sISO on the development of breast cancer. Whether sISO positively or negatively affect the tumorigenesis of the mammary gland presumably is dependent on the time point of the sISO exposure. An exposure during gestation, lactation as well as prepubertal is believed to be preventive whereas an exposure later in life might be adverse.
Objective: Aim of the study was to assess whether and how sISO influence the development of breast cancer. Therefore, August-Copenhagen-Irish (ACI) rats, a model for estrogen driven carcinogenesis, were exposed towards sISO. Dietary exposure was started preconceptional and maintained in offspring animals continuously throughout the whole individual life.
Experimentals: All ACI rats were kept under controlled conditions and had ad libitum access either to a sISO-free control diet or a diet supplemented with 500ppm of the Novasoy®650 extract. Pregnant females were kept under the established dietary regimen throughout gestation and lactation period and the female offspring was investigated in the following experimental procedures. On postnatal day 60 (PND60) the animals of each dietary group randomly were implanted a 17beta-estradiol (E2) releasing (approximately 2mg release in 90 days) or a placebo pellet to induce tumorigenesis of the mammary gland. The rats were weekly palpated for mammary tumors and weighed weekly for the duration of the experiment (until PND240). Finally, we assessed physiological (e.g. organ weights, sISO exposition, mammary gland areas), (patho-)histological (HE staining), immunohistological (PCNA expression) as well as molecular end points (gene expression) of the resulting mammary gland phenotypes.
Results: Control diet animals had a daily sISO exposure of ∼0.5mg/kg body weight, whereas animals of the Novasoy®650 group had a daily exposure of ∼30mg/kg body weight. Independent of the dietary background, none of the animals with an implanted placebo pellet showed tumor precursors. Ductual carcinomas in situ (DCIS) were detected in 83.3% of the animals of the control diet and in 100% of the animals of the Novasoy®650 diet, both following implantation of an E2-release pellet. Moreover, control diet animals exposed to E2 had significantly reduced mammary gland areas compared to the respective placebo group. This difference was not detectable in the Novasoy®650 dietary group. Additionally, no differences in the uterus as well as liver wet weights were noticed. On a molecular level, the expression of several genes responsible for proliferation (Ki67), estrogenicity (Tff1) and cell cycle control (Cdk4) were modified in animals lifelong exposed towards sISO.
Conclusions: In ACI rats, a prenatally started and lifelong maintained sISO exposure clearly affects the estradiol induced malignant transformation of the mammary gland. This is evidenced by a higher number of DCIS as well as increased proliferation levels which were found in animals chronically exposed to sISO.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-09-03.