Factors that promote the development of human breast cancer

Epidemiologic and endocrinologic studies of breast cancer etiology are reviewed in the context of the Moolgavkar two-stage model for mammary carcinogenesis. Promoters are hypothesized to enhance the growth of stem and intermediate cells, and initiators are assumed to cause stem and intermediate cells to give rise to intermediate and tumor cells, respectively. Although all epidemiologic features of breast cancer can be explained in terms of the cellular events supposed by the model, the specific causes of breast cancer are largely unknown. Aberrations in endogenous steroid sex hormones most probably act as promoters, although their exact nature and etiology are unclear. Ionizing radiation is the only known initiator. The two-stage model implies that others exist and that they are responsible for both the international variation in risk of breast cancer, and its familial aggregation. Results of endocrinologic studies suggest either that aberrations in endogenous sex hormones serve as such initiators or are correlated with them, or that familial and international variations in risk are mediated by promoters.