Cell proliferation and apoptosis during mammary carcinogenesis in pituitary isografted mice

In the present study, pituitary isografted animals serve as a model for evaluating the changes in differentiation, cell proliferation and programmed cell death (apoptosis) in mammary epithelial cells during carcinogenesis. The percentage of bromodeoxyuridine (BrdU)-labeled ductal and alveolar cells was significantly higher in pituitary isografted animals than in non-isografted control animals. BrdU-labeled cells increased in lobular hyperplastic nodules, keratinized nodules and mammary carcinomas; similar changes were observed with apoptotic cells, which were rare in mammary glands of adult non-isografted animals (one to three apoptotic cells per 2000 mammary epithelial cells), but their number increased in hyperplastic lesions and mammary carcinomas. Among hyperplastic nodular lesions, variants with high, moderate and low proliferative activity and/or apoptotic cell death were identified, which suggests that they may have different growth potentials and different propensities for malignant transformation. After removing pituitary isografts, apoptosis occurs in hyperplastic lesions but not in mammary carcinomas-implying that malignant tumors are hormone-independent. The dynamics of the changes in apoptotic cell death among various hyperplastic lesions after removal of pituitary isografts suggests that these lesions are composed of heterogeneous cell populations, as far as the initiation of apoptosis is concerned. Our data indicate that apoptosis can be used together with cell proliferation as a potential marker in characterizing the growth potential and phenotypic diversity of hyperplastic, premalignant and malignant mammary gland lesions.