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 Our most recent (and unpublished) data shows that tamoxifen administration during the risk window (8-16 weeks) completely prevents cancer development in this model system.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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA089018-01
Application #
6401966
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Jordan, V Craig (2015) The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer 22:R1-31
Arora, Hans C; Jensen, Mark P; Yuan, Ye et al. (2012) Nanocarriers enhance Doxorubicin uptake in drug-resistant ovarian cancer cells. Cancer Res 72:769-78
Wu, Aiguo; Paunesku, Tatjana; Zhang, Zhuoli et al. (2011) A Multimodal Nanocomposite for Biomedical Imaging. AIP Conf Proc 1365:379
Thurn, Kenneth T; Arora, Hans; Paunesku, Tatjana et al. (2011) Endocytosis of titanium dioxide nanoparticles in prostate cancer PC-3M cells. Nanomedicine 7:123-30
Morrow, Monica; Chatterton Jr, Robert T; Rademaker, Alfred W et al. (2010) A prospective study of variability in mammographic density during the menstrual cycle. Breast Cancer Res Treat 121:565-74
Chatterton Jr, Robert Treat; Parker, Noah P; Habe-Evans, Mito et al. (2010) Breast ductal lavage for assessment of breast cancer biomarkers. Horm Cancer 1:197-204
Patel, Roshani R; Sengupta, Surojeet; Kim, Helen R et al. (2010) Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors. Eur J Cancer 46:1537-53
Balaburski, Gregor M; Dardes, Rita C; Johnson, Michael et al. (2010) Raloxifene-stimulated experimental breast cancer with the paradoxical actions of estrogen to promote or prevent tumor growth: a unifying concept in anti-hormone resistance. Int J Oncol 37:387-98
Wolin, Kathleen Y; Colangelo, Laura A; Chiu, Brian C-H et al. (2009) Obesity and immigration among Latina women. J Immigr Minor Health 11:428-31
Thurn, Kenneth T; Paunesku, Tatjana; Wu, Aiguo et al. (2009) Labeling TiO2 nanoparticles with dyes for optical fluorescence microscopy and determination of TiO2-DNA nanoconjugate stability. Small 5:1318-25

Showing the most recent 10 out of 163 publications