The increasing incidence of breast cancer in the Western world and the lack of identification of a specific etiologic agent of this disease, has led researchers to identify both endogenous and exogenous factors which might be indicative of a greater risk of disease development. The most clearly identified endogenous risk factors are age, nulliparity and older age at first full term pregnancy. Exogenous factors suspected to contribute to higher breast cancer risk, although not proven as yet, are environmental chemical carcinogens. The study of the pathogenesis of rat mammary carcinomas induced by polycyclic aromatic hydrocarbons (PAHs) have clarified how endogenous factors interact with the exogenous ones for determining a greater susceptibility of the breast to cancer development. Chemical carcinogens are capable of transforming mammary epithelial cells of the young virgin rat because of their undifferentiated condition, high rate of cell proliferation and sensitivity to be stimulated for growth by the hormones and growth factors produced during puberty. The observation that the same carcinogens fail to transform the differentiated epithelium of the parous rat mammary gland indicates that differentiation induced through pregnancy and lactation significantly reduces the gland's neoplastic potential. Epidemiologic observations confirm that full term pregnancy, if completed before age 24, protects women from breast cancer development. Differentiation plays a key role in carcinogenesis because it reduces the high cell proliferative activity observed in lobules type 1 or terminal ductal lobular units (TDLUs), known site of origin of breasts carcinomas. Based upon the observation that carcinogens induce a greater oncogenic response in dividing than in non-dividing cells, what places great emphasis on the rate of cell proliferation and on the population of cells that are in the late G/1 or S phases of the cell cycle, which represent the peak of maximal sensitivity to transformation, we postulate that young, nulliparous females between the ages of 14 and 24 years, in whom the gland has a low degree of differentiation, and with topographic areas of high proliferation represent a group of women at greater risk for cell transformation. We propose to test the hypotheses that chemical carcinogens are capable of transforming human breast epithelial cells when they fulfill specific conditions determined by their basic level of differentiation and cell proliferation. A second postulate is that the undifferentiated cells of young nulliparous women responds to carcinogens with activation of specific genes that control cell proliferation, such as those of the cyclin family or inhibition of programmed cell death, such as bcl-2, and that these changes lead to cell transformation, and third, that the differentiated cell of parous women respond to chemical carcinogen exposure with activation of programmed cell death (apoptosis), thus protecting the breast from neoplastic development. These hypotheses will be tested by challenging with two different chemical carcinogens human breast epithelial cells obtained from four groups of women: young nulliparous and young parous women (ages 14-45), and old nulliparous and old parous women (ages 46-65). Results obtained through these studies will contribute to clarify how the basic conditions of the host modulate the response of the mammary epithelium to environmental carcinogens and what genes need to be activated for the initiation of the neoplastic process.
