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RFA CA-03-001: Cooperative Grants for Nutritional Modulation of Genetic Pathways Leading to Cancer

Lombardi Cancer Center
Department of Oncology
Georgetown University
Washington, DC

Leena Hilakivi-Clarke, PhDPrincipal Investigator
Leena Hilakivi-Clarke, PhD

Project Summary

"Timing of Dietary Estrogenic Exposures and Breast Cancer Risk."

The aim is to develop novel ways to prevent some breast cancers by dietary changes during pregnancy and puberty. The timing of exposures to nutritional components that interact with hormone receptors at the molecular level will be studied, particularly phytoestrogens, n-3 polyunsaturated fatty acids, and vitamins A and D. Associated mechanisms, such as changes in estrogen receptors, also will be investigated.

Project 1 Timing of Dietary Estrogenic Exposures and Breast Cancer Risk: Role of Estrogen Receptors and Tumor Suppressors

Overall Goal

To determine how prepubertal and pregnancy exposures to dietary estrogens mediate their effects on breasts.

Specific Goals

  • To establish if prepubertal exposure to the dietary estrogens present in soy and/or n-3 PUFA will reduce sporadic mammary tumorigenesis.
  • To ascertain if prepubertal exposure to genistein and/or n-3 PUFAs increases BRCA1 expression, which in turn alters expression of genes regulated by this tumor suppressor, including ER-a and cyclin D1, and consequently, if prepubertal exposure to estrogens will increase the risk of breast cancer in BRCA1 mutant mice.
  • To determine if an exposure during pregnancy to estrogens and dietary estrogens increases mammary tumorigenesis in dams who either have acquired mutations in tumor suppressor genes or otherwise have undergone first events of malignant transformation.

Project 2 Timing of Vitamin A and D Exposures and Breast Cancer: Mechanism of Action

Overall Goal

  • To determine whether timing and duration of exposure to vitamins A and D modulate the development of breast cancer and to determine the molecular pathways by which vitamins A and D exert their anti-cancer effect.

Specific Goals

  • To investigate the significance of the timing of vitamins A and D exposure in the development of breast cancer in animal models.
  • To investigate the molecular mechanism, whereby vitamins A and D affect the development of breast cancer.
  • To investigate the significance of the vitamin D receptor (VDR) in the development of breast cancer cells in VDR knockout mice.

Project 3 Early Life Exposures to Phytoestrogens and Mammary Tumorigenesis

Overall Goal

  • To examine whether in utero and prepubertal exposure to either genistein or enterolactone influences mammary tumorigenesis through ER-associated mechanisms.

Specific Goals

  • To determine whether early life exposure results in permanent changes in ER expression, including their coregulators, resulting in changes in epithelial proliferation, differentiation, and relevant gene expression profiles.
  • To examine whether differences in ER expression are associated with differences in mammary tumor development.
  • To examine whether early exposure to genistein or enterolactone causes changes in proliferative activity and susceptibility to mammary tumor development.

Project 4 Effect of Birth Weight, Weight During Childhood and Pregnancy Weight Gain on Familial Breast Cancer Risk

Goal

  • To determine whether biomarkers of high in utero, childhood and pregnancy estrogenicity, relevant to dietary exposures, are associated with increased familial breast cancer risk in Finnish Women.

Pilot Project 1 Effects of Dietary Intervention on Pregnancy Weight Gain

Goal

  • To test the hypothesis that health counseling, including dietary recommendations to increase fruit, vegetable and fiber consumption and reduce saturated fat intake prevents an excessive pregnancy weight gain has a favorable effect on putative biological markers of breast cancer risk.

Pilot Project 2 Prepubertal Exposure to Selenium and Breast Cancer Risk

Goals

  • To determine whether prepubertal exposure to dietary amounts of selenium protects animals against chemically induced mammary tumors.
  • To determine whether the protective effects of selenium are due to its ability to activate the estrogen receptor.

Research is supported by three cores:

Core A

Administrative

Core B

Statistics and Microarray

Core C

Bioresources

References

Olivo SE, Hilakivi-Clarke L. Opposing effects of prepubertal low and high fat n-3 polyunsaturated fatty acid diets on rat mammary tumorigenesis. Carcinogenesis 2005;26:1563-72.

Trock BJ, Hilakivi-Clarke L, Clarke R. Meta-Analysis of soy intake and breast cancer risk. JNCI  2006;98:459-71.

De Assis S, Khan G, Hilakivi-Clarke L. High birth weight increases mammary tumorigenesis in rats. Int J Cancer 2006;119(7):1537-46.

De Assis S, Wang M, Goel S, et al. Increased carcinogen-induced mammary tumorigenesis and activation of MAPK in obese (fa/fa) Zucker rats exposed to pregnancy hormonal environment. J Nutr 2006;136:998-1004.

Hilakivi-Clarke L, Olivo SE, Shajahan A, et al. Mechanisms mediating the effects of prepubertal (n-3) polyunsaturated fatty acid diet on breast cancer risk in rats. J Nutr2005 Dec;135(12 Suppl):2946S-2952S.

Yu B, Khan G, Hilakivi-Clarke L. Maternal dietary exposure to fiber during pregnancy and mammary tumorigenesis among rat offspring. Int J Cancer 2006;119(10)2279-86.

Shah S, Islam MN, Dakshanamurthy S, et al. The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell 2006 Mar 17;21(6):799-809.

Smeds AI, Hakala K, Hurmerinta TT, et al. Determination of plant and enterolignans in human serum by high-performance liquid chromatography with tandem mass spectrometric detection. J Pharm Biomed Anal 2006;41(3):898-905.

Saarinen NM, Penttinen PE, Smeds AI, et al. Structural determinants of plant lignans for growth of mammary tumors and hormonal responses in vivo. J Steroid Biochem Mol Biol 2005 Feb;93(2-5):209-19. Epub 2005 Feb 1.

Smeds AI, Saarinen NM, Eklund PC, et al. New lignan metabolites in rat urine. J Chromatogr B Analyt Technol Biomed Life Sci2005 Feb 25;816(1-2):87-97.

Kotsopoulos J, Olopado OI, Ghadirian P, et al. Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res2005;7(5):R833-43. Epub 2005 Aug 19.

Rosen EM, Fan S, Isaacs C. BRCA1 in hormonal carcinogenesis: basic and clinical research. Endocr Relat Cancer 2005 Sep;12(3):533-48. Review.

Kinnunen Ti, Pasanen M, Aittasalo M, et al. Preventing excessive weight gain during pregnancy – a controlled trial in primary health care. Eur J Clin Nutr 2007 Jan 17; [Epub ahead of print]

Hilakivi-Clarke L, Luoto R, Huttunen T, Koskenvuo M. Pregnancy weight gain and premenopausal breast cancer risk. J Reprod Med 2005 Nov;50(11):811-6.

Albanese C, Rodriguez O, Johnson M, Fricke S. Models of Prostate Cancer. Drug Discovery: Disease Models 2005;2(1) 7-13.

Fricke S, Rodriguez O, VanMeter J, et al. In Vivo Magnetic Resonance Volumetric and Spectroscopic Analysis of Mouse Prostate Cancer Models. Prostate 2006 May 15;66(7):708-17.

Rodriguez O, Fricke S, Chien C, et al. Contrast-enhanced in vivo imaging of breast and prostate cancer cells by MRI. Cell Cycle 2006;4;5(1) 113-119

Leslie K, Lang C, Devgan G, et al. Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Research 2006 Mar 1;66(5):2544-2552.

Wang Z, Wang Y, Xuan J, et al. Optimized multilayer perceptrons for molecular classification and diagnosis using genomic data. Bioinformatics 2006;22: 755-761.

Xuan J, Hoffman E, Clarke R, Wang Y. Normalization of microarray data by iterative nonlinear regression. 5th IEEE Symposium on Bioinformatics and Bioengineering (BIBE'05), pp. 267-270, 2005.

Zhu Y, Singh B, Hewitt S, et al. Expression patterns among interferon regulatory factor-1, human X-box binding protein-1, nuclear factor kappa B, nucleophosmin, estrogen receptor-alpha and progesterone receptor proteins in breast cancer tissue microarrays. Int J Oncol 2006;28:67-76.

Riggins RB, Bouton AH, Liu MC, Clarke R. Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer. Vitam Horm 2005;71:201-37.

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