Breast cancer is likely the result of the interaction of several factors, all of which must be present for cancer to be manifested. The understanding of breast cancer requires a further knowledge of the factors regulating the susceptibility of the organ to carcinogenesis, which requires the demonstration that transformation from normal to neoplastic takes place under the influence of a given etiological agent, which could be a chemical carcinogen. Therefore this proposal intends to answer the following questions: (i) Is the human breast epithelium susceptible to neoplastic transformation by the chemical carcinogens that are known to cause cancer in experimental animals? (ii) if the human mammary gland is susceptible to neoplastic transformation in vitro, what are the biological parameters that regulate this susceptibility? and (iii) is the susceptibility to tranformation determined by the patient's reproductive history, a factor known to affect the development of breast cancer in vivo? These studies will be carried out using primary cultures or early passages of human breast epithelium from tissue obtained at surgery or from recent post-mortem specimens from three groups of women: (a) parous, premenopausal women with an early full term pregnancy (before age 24 years), known to be at low risk for development of breast cancer, (b) nulliparous, premenopausal women age-matched with group a, known to have four times higher risk than the former of developing breast carcinoma and (c) young nulliparous women between ages 12-14 years in whom the mammary gland is relatively undifferentiated and therefore likely to be more susceptible to carcinogenesis. The cells will be treated with two chemical carcinogens, (DMBA and MNU) which have different metabolic pathways of activation but the same effect in inducing mammary carcinoma in experimental animals. Neoplastic transformation will be measured by the expression of phenotypic changes and by tumorigenicity in heterologous hosts.
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