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Timing of dietary fat exposure and mammary tumorigenesis: Role of estrogen receptor and protein kinase C activity

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Molecular and Cellular Effects of Nutrition on Disease Processes

Part of the book series: Developments in Molecular and Cellular Biochemistry ((DMCB,volume 26))

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Abstract

The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a high-fat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in the serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high-fat diet. Furthermore, the administration of estradiol to pregnant dams produces effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters’ breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity. (Mol Cell Biochem 188: 5–12, 1998)

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Authors and Affiliations

  1. Lombardi Cancer Center, Georgetown University, Washington, DC, USA

    Leena Hilakivi-Clarke & Robert Clarke

  2. Department of Psychiatry, Georgetown University, Washington, DC, USA

    Leena Hilakivi-Clarke

  3. Department of Physiology, Georgetown University, Washington, DC, USA

    Robert Clarke

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  1. Leena Hilakivi-Clarke
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Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre, 351 Tache Avenue, Winnipeg, Manitoba, Canada, R2H 2A6

    Grant N. Pierce

  2. Department of Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara Kanagawa 228, Japan

    Tohru Izumi (Professor and Chairman) (Professor and Chairman)

  3. Medizinische Forschung Philipps University of Marburg, Karl-von-Frisch-Str., 135033, Marburg, Germany

    Heinz Rupp

  4. INRA, Lipides Membranaires et Fonctions Cardiovasculaires Faculté des Sciences Pharmaceutiques et Biologiques, 4 Av de l’Observatoire, 75270, Paris Cedex 06, France

    Alain Grynberg

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Hilakivi-Clarke, L., Clarke, R. (1998). Timing of dietary fat exposure and mammary tumorigenesis: Role of estrogen receptor and protein kinase C activity. In: Pierce, G.N., Izumi, T., Rupp, H., Grynberg, A. (eds) Molecular and Cellular Effects of Nutrition on Disease Processes. Developments in Molecular and Cellular Biochemistry, vol 26. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5763-0_1

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