Developmental, cellular, and molecular basis of human breast cancer

Breast cancer, which is the most common neoplastic disease in females and accounts for up to one third of all new cases of women's cancer in North America, continues to rise in incidence. In addition, the mortality caused by this disease has remained almost unchanged for the past 5 decades, becoming only second to lung cancer as a cause of cancer-related death. The failure in eradicating this disease is largely due to the lack of identification of a specific etiologic agent, the precise time of initiation, and the molecular mechanisms responsible for cancer initiation and progression. Despite the numerous uncertainties surrounding the origin of cancer, there is substantial evidence that breast cancer risk relates to endocrinologic and reproductive factors. The development of breast cancer strongly depends on the ovary and on endocrine conditions modulated by ovarian function, such as early menarche, late menopause, and parity. However, the specific hormone or hormone combinations responsible for cancer initiation have not been identified, and their role as protective or risk factors is still incompletely understood. A highly significant female hormone is estrogen, which is involved in the development of a variety of cancers, but it is still unclear whether estrogens are carcinogenic to the human breast. An understanding of whether estrogens cause mutations, and, if so, whether they act through hormonal effects activated by receptor binding, cytochrome P450-mediated metabolic activation, or compromise the DNA repair system, is essential for determining whether this steroid hormone is involved in the initiation or progression of breast cancer. This knowledge has to be based on a multidisciplinary approach encompassing studies of the development of the breast, influence of hormones on the differentiation of individual structures, and their interrelations in the pathogenesis of breast cancer. The analysis of the mechanisms involved would require confirmation in the adequate in vitro models and determination of the role played by genomic alterations in both cancer initiation and progression.