Abstract PD02-03: Regulation of Mammary Stem Cell Population with Dietary Intake of Soy Protein Isolate Reveals Novel Mechanisms for Diet-Mediated Control of Mammary Tumorigenesis
Authors: Rahal OM , Pabona JMP , Su Y , Fox RS , Hennings L , Rogers T , Nagarajan S , Simmen RCM. 
Published: April 2011

Breast cancer risk is highly modified by environmental factors including diet. Previously, we showed that dietary intake of soy protein isolate (SPI) decreased mammary tumor incidence and increased mammary tumor latency in rats relative to those fed a control casein (CAS) diet, when exposed to the chemical carcinogen NMU. Mammary tumor preventive effects by SPI were associated with up-regulation of the tumor suppressor PTEN and down-regulation of the oncogenic Wnt-signaling components in mammary epithelial cells (MECs) leading to enhanced differentiation. Given that breast cancer is considered to be initiated by stem cells (SCs) with tumorigenic potential, termed cancer stem cells (CSCs), and mammary over-expression of Wnt-1 in mice causes spontaneous breast tumors due to the expansion of mammary CSCs, we hypothesized that diet may alter the mammary SC population to effect mammary tumor prevention. Here, we investigated SPI effects relative to CAS, on mammary tumor development in MMTV-Wnt 1-Transgenic (Tg) female mice and on the mammary SC population in virgin wildtype (WT) and pre-neoplastic Tg female mice. Tumor incidence at 8 months of age of Tg mice fed SPI (n=30) post-weaning was lower than in those fed CAS (48.3% vs.73.5%; P&lt;0.05) (n=34). Interestingly, tumor latency in SPI-fed Tg mice was shorter than for the CAS-fed group (4.65 vs. 5.88 months; P&lt;0.05). Tumor weight and growth rate was similar for the diet groups. To evaluate SPI effects relative to CAS, on mammary SC population, epithelial cells from mammary tissues were isolated from WT (PND 100) and Tg (PND75) mice. The percentage of mammary SCs was quantified by fluorescence activated cell sorting analysis of MECs based on their expression of mouse mammary SC markers (CD29 and CD24) within the Lineage negative (Lin-) population (CD45-, TER119-, CD31-). The Lin-CD29hiCD24hi subpopulation in MECs was decreased by 50% in Tg mice fed SPI post-weaning relative to those fed CAS, decreasing the likelihood of mutations that convert normal to cancer SC and could explain the protective effects of SPI on tumor incidence. Interestingly, the SC population was expanded by 2-fold in MECs of WT mice fed SPI relative to the CAS group, which could be beneficial for mammary gland development and tissue homeostasis. Our findings provide the first report of dietary effects on the SC population in MECs in vivo. The dichotomy of SPI effects on tumor outcome in mammary tissues with dysregulated Wnt signaling maybe related to the loss of the complex regulatory grid between PTEN and Wnt/β-catenin pathways, both of which control stem cell fate. The possibility that diet can influence tumor progression at the level of the SC population suggests the important contribution of nutrition to the etiology of breast cancer and to the early management of breast health. Supported by USDA-ARS and Department of Defense Breast Cancer Research Program.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-03.