The breast develops an array of benign and malignant lesions which become manifest at maturity. These lesions do not arise in a random fashion but they develop in certain specific areas of the breast. From 40-50% of infiltrating ductal carcinomas, the most common breast malignancy, as well as benign lesions such as adenomas and fibrocystic disease, develop preferentially in the upper external quadrant of the breast. There is as yet no explanation for the tendency of these lesions to cluster in such specific topographic area, however, it is postulated that the susceptibility of the upper external quadrant to develop a higher number of neoplasms is modulated by variations in local developmental patterns and differentiation. There is evidence that supports this hypothesis, such as: 1) the breast of young, post-pubertal females possesses a higher number of undifferentiated structures in the upper external than in the other quadrants of the organ; 2) malignant lesions develop in undifferentiated terminal ductal structures; and 3) the presence of undifferentiated structures in the mammary gland associates with the expression of phenotypic changes of cell transformation after in vitro treatment of epithelial cells with chemical carcinogens. Furthermore, experimental data demonstrate that chemically-induced rat mammary cancer occurs when the carcinogen selectively affects the undifferentiated terminal end buds that are more frequently present in the distal portions of thoracic mammary glands of virgin animals. These studies showed that carcinogenic initiation is modulated by gland topography, degree of glandular development and cell kinetic characteristics of the mammary epithelium, suggesting that the pattern of glandular development plays an important role in the breast's lifetime risk of developing neoplasms. The thrust of this proposal is to study in a systematic manner the developmental pattern of the breast from prepuberty to the early adult years, to assess breast development and differentiation in the various topographic areas of the organ, to determine whether variations in cell kinetics are a function of topographic differences in gland development, how pregnancy modifies the pattern of breast development and lastly, whether the development of malignant lesions in the various quadrants of the breast correlates with the number of undifferentiated structures present in those given areas. This knowledge will lay the basis for understanding the role played by gland development and differentiation on the susceptibility of the human breast to malignant transformation.
