Location: Arkansas Children's Nutrition CenterTitle: Regulation of mammary stem cell population with dietary intake of soy protein isolate reveals novel mechanisms for diet-mediated control of mammary tumorigenesis Author
|John Mark, Pabona|
Submitted to: Cancer Research
Publication Type: Abstract Only
Publication Acceptance Date: 9/9/2010
Publication Date: 12/15/2010
Citation: Rahal, O., John Mark, P., Su, Y., Fox, R., Hennings, L., Rogers, T., Nagarajan, S., Simmen, R.C. 2010. Regulation of mammary stem cell population with dietary intake of soy protein isolate reveals novel mechanisms for diet-mediated control of mammary tumorigenesis. Cancer Research. 70(24):99s. Interpretive Summary:
Technical Abstract: 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 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=32) was lower than those fed CAS (51.6% vs.71%; p=0.08) (n=33). Interestingly, tumor latency in SPI-fed Tg mice was shorter than for the CAS-fed group (4.4 vs. 5.6 months; P<0.05). Tumor 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 expanded by two-fold in WT mice fed SPI post-weaning relative to those fed CAS. Similarly, the SC population was increased by 1.5-fold in MECs of Tg mice fed SPI relative to the CAS group. Mammary glands of WT mice exposed to SPI had higher levels of tumor suppressor PTEN and E-cadherin proteins at puberty (PND35) and at adulthood (PND50) and lower beta-catenin protein expression at PND50, over those of the CAS group. 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/beta-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.