The continuing goal of this project is to define the oncogenic effects of radiation on the mammary glands at the cellular and sub-cellular levels. Mammary cancer is a major malignant disease among American women and a major cause of morbidity and mortality among those exposed to ionizing radiation. We hypothesized that the mammary cells from which malignant tumors arise are the same clonogenic cell sub-population necessary to tissue repair and repopulation following radiation injury. We have developed quantitative rat mammary cell transplantation and endocrine manipulation procedures and short- term culture techniques to measure the concentration of mammary clonogens, i.e. the cells which when transplanted to hormonally modified recipients give rise to multi-cellular clonal glandular units. With these techniques we have defined the radiation dose-survival response of mammary clonogens after exposure to radiation, and have demonstrated that radiogenic initiation of cancer is a common cellular event and is dependent on the number of clonogenic cells present at the time of radiation exposure. During this grant period, we will: 1) determine whether the radiation-induced initiating lesion is repairable; 2) quantitate the relationship between initiated cell number, radiation dose and carcinoma incidence; 3) determine the effect of donor age on the susceptibility of the mammary clonogens to radiogenic initiation; 4) further purify the clonogenic cells and their properties; and 5) investigate karyotypic changes in the clonogens and their progeny during promotion/progression to overt cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Radiation Study Section (RAD)
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University of Wisconsin Madison
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Kim, N D; Oberley, T D; Yasukawa-Barnes, J et al. (2000) Stem cell characteristics of transplanted rat mammary clonogens. Exp Cell Res 260:146-59
Kamiya, K; Gould, M N; Clifton, K H (1998) Quantitative studies of ductal versus alveolar differentiation from rat mammary clonogens. Proc Soc Exp Biol Med 219:217-25
Kim, N D; Paik, K J; Clifton, K H (1996) Inhibitory effects of retinoids on development of squamous metaplasia in rat mammary epithelial organoids cultured in Matrigel. Cancer Lett 110:217-23
Clifton, K H (1996) Comments on the evidence in support of the epigenetic nature of radiogenic initiation. Mutat Res 350:77-80
Kamiya, K; Yasukawa-Barnes, J; Mitchen, J M et al. (1995) Evidence that carcinogenesis involves an imbalance between epigenetic high-frequency initiation and suppression of promotion. Proc Natl Acad Sci U S A 92:1332-6
Shimada, Y; Yasukawa-Barnes, J; Kim, R Y et al. (1994) Age and radiation sensitivity of rat mammary clonogenic cells. Radiat Res 137:118-23
Kim, N D; Clifton, K H (1993) Characterization of rat mammary epithelial cell subpopulations by peanut lectin and anti-Thy-1.1 antibody and study of flow-sorted cells in vivo. Exp Cell Res 207:74-85
Kim, N D; Oberley, T D; Clifton, K H (1993) Primary culture of flow cytometry-sorted rat mammary epithelial cell (RMEC) subpopulations in a reconstituted basement membrane, Matrigel. Exp Cell Res 209:6-20
Kamiya, K; Kim, N D; Gould, M N et al. (1991) Repair of potentially lethal damage in rat mammary clonogens following irradiation in organoid culture. Int J Radiat Biol 59:1207-16
Kamiya, K; Clifton, K H; Gould, M N et al. (1991) Control of ductal vs. alveolar differentiation of mammary clonogens and susceptibility to radiation-induced mammary cancer. J Radiat Res (Tokyo) 32 Suppl 2:181-94

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