Epidemiological studies have not consistently linked any specific dietary component to either an increased or reduced breast cancer risk. We propose that this is partly due to the incomplete consideration that timing of dietary exposures might be more important in affecting the risk than an exposure shortly before or at diagnosis. We further propose that the breast is most sensitive to dietary factors at times when diet-induced biological changes can alter its development and function. These sensitive periods include fetal life, puberty, and pregnancy, when the breast undergoes extensive proliferation following a natural exposure to high levels of hormones and growth factors. Steroid hormones and their nuclear receptors are known to play a central role in breast cancer. In this U54 program, we will focus on studying the timing of exposures to nutritional components that interact with nuclear hormone receptors. In three first Projects (P-I to P-Ill) by Drs. Hilakivi-Clarke (P-I), Byers (P-II) and Makela (P-Ill), we will explore whether timing of dietary exposures to phytoestrogens, n-3 polyunsaturated fatty acids and vitamins A and D alter mammary tumorigenesis and the mechanisms mediating these associations. The mechanisms include changes in estrogen receptor (ER) a and ERb, BRCA1, cyclin D1, and b-catenin. Animal models that mimic both sporadic and familial breast cancers will be used. The projects will interact with each other in several fronts. Two epidemiological projects by Drs. Nevanlinna and Luoto (P-IV) and Dr. Fogelholm (Pilot I) will examine whether timing of excessive energy intake affects the risk of developing familiar breast cancer, and whether dietary intervention to prevent excessive weight gain during pregnancy reduces breast cancer risk. The epidemiological projects will interact with P-I and Pilot II. Pilot II by Dr. Martin will study the role of ERa in mediating the effects of selenium on the breast. Three core facilities are also included: Administrative Core, Biostatistics and Microarray Core, and Bioresources Core. This program aims to develop novel means to prevent some breast cancers by dietary modifications that take place during pregnancy and puberty.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
3U54CA100970-05S1
Application #
7691852
Study Section
Special Emphasis Panel (ZCA1-SRRB-Q (J1))
Program Officer
Milner, John A
Project Start
2003-09-22
Project End
2009-08-31
Budget Start
2007-09-20
Budget End
2009-08-31
Support Year
5
Fiscal Year
2008
Total Cost
$50,000
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Parodi, Daniela A; Greenfield, Morgan; Evans, Claire et al. (2015) Alteration of mammary gland development and gene expression by in utero exposure to arsenic. Reprod Toxicol 54:66-75
Cook, Katherine L; Wärri, Anni; Soto-Pantoja, David R et al. (2014) Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin Cancer Res 20:3222-32
Hilakivi-Clarke, Leena (2014) Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters. Breast Cancer Res 16:208
Davis, Jennifer; Khan, Galam; Martin, Mary Beth et al. (2013) Effects of maternal dietary exposure to cadmium during pregnancy on mammary cancer risk among female offspring. J Carcinog 12:11
Hilakivi-Clarke, Leena; de Assis, Sonia; Warri, Anni (2013) Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk. J Mammary Gland Biol Neoplasia 18:25-42
de Assis, Sonia; Warri, Anni; Cruz, M Idalia et al. (2012) High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring. Nat Commun 3:1053
de Assis, Sonia; Warri, Anni; Benitez, Carlos et al. (2011) Protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on BRCA1 expression. Cancer Prev Res (Phila) 4:1436-48
Nielsen, Tina S; Khan, Galam; Davis, Jennifer et al. (2011) Prepubertal exposure to cow's milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats. Int J Cancer 128:12-20
Divekar, Shailaja D; Storchan, Geoffrey B; Sperle, Katherine et al. (2011) The role of calcium in the activation of estrogen receptor-alpha. Cancer Res 71:1658-68
de Assis, Sonia; Warri, Anni; Cruz, M Idalia et al. (2010) Changes in mammary gland morphology and breast cancer risk in rats. J Vis Exp :

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