Hormones are known to play a crucial role in mammary cancer development. Diets rich in soy-based products of restricted in calories have been associated with a reduction in breast cancer incidence. This protective effect may be the result of modulation of estrogen metabolism or action. These factors are difficult to control and costly to study in humans. Furthermore, these studies do not lend themselves to analyses of mechanisms of gene expression using currently available technologies. The recent development of transgenic mouse models make such clinically important studies feasible using surrogate systems. Utilizing virgin MMTV wt erbB-2 transgenic mice, which are genetically susceptible to breast cancer, we have demonstrated a co-carcinogenic and dose- dependent effect of 17-beta-estradiol administered during the risk window. Our data suggests that 17-beta- estradiol (E2) accelerates mammary epithelial hyperplasia and dysplasia in concert with down- regulation of the estrogen receptor (ER), over-expression of erbB-2, activated erbB-2, EGFR and TGFalpha. Cancers which arises in transgenic mice given E2 supplementation (and novel tumor cell lines from these tumors) have phenotypic, biologic and molecular differences when compared to breast tumors of untreated animals. Whole mount preparations, in particular, demonstrated marked abnormalities in breast morphogenesis in parallel with these biologic changes. Our most recent (and unpublished) data shows that tamoxifen administration during the risk window (8-16 weeks) completely prevents cancer development in this model system. Soy diet, as compared to casein diet, reduces and delays breast carcinogenesis as well.
Our specific aims are: 1) To confirm that dietary soy prolongs tumor latency and decreases the risk of carcinogenesis in virgin MMTV wt erbB-2 transgenic mice, which are genetically predisposed to breast cancer, using rigorously matched formulary diets (soy vs. casein) with and without exogenous 17-beta estradiol (E2) administration and tamoxifen; 2) to determine the effects of calorie restriction in virgin MMTV wt erbB-2 transgenic mice, with and without exogenous 17-beta- estradiol (E2) administration and tamoxifen; 2) to determine the effects of calorie restriction in virgin MMTV wt erbB- 2 transgenic mice, with and without exogenous 17-beta-estradiol (E2) estradiol (E2) administration (single pellet, during the risk window) on breast carcinogenesis using several additional transgenic and bi- transgenic mice including: MMTV-Wnt 1, MMTV erbB-2 X mutant p53; MMTV erbB-2 X MMTV TGFalpha. To our knowledge our studies are the first to link hormones to cancer in this model system and show prevention using tamoxifen. Furthermore, we are the first to suggest that transgenic models may demonstrate differences in tumor latency with soy based (phytoestrogen rich) diet. These models will further elucidate interactions between hormones, diet and cancer and will allow molecular analyses to better define genetic and expression differences which may be associated with these factors.
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