Breast cancer accounts for up to one third of all new cases of women's cancer in North America, representing the most common neoplastic disease in the female. While its incidence continues to rise, the mortality rate from breast cancer has remained almost unchanged in the past five decades, becoming second only to lung cancer as a cause of cancer deaths.
Intensive epidemiological studies have identified a number of biological and social traits as risk factors associated with breast cancer, including evidence of the BRCA1 susceptibility gene, familial history of cancer in the breast, ovary or endometrium, individual history of breast diseases, early onset of menstruation, nulliparity or delayed first childbirth, short duration of breast feeding, late menopause, advanced age, postmenopausal obesity, higher socio-economical status, excess ionizing radiation, tallness in adult life, consumption of alcohol, extended use of oral contraceptives and prolonged estrogen replacement therapy. Hormonal influences have been attributed mainly to the unopposed exposure to elevated levels of estrogens. The mechanisms through which this phenomenon occurs, however, have not been completely understood, as has been indicated for a variety of female cancers, namely vaginal, hepatic and cervical carcinomas. However, it is still unclear whether estrogens are carcinogenic to the human breast.
Most of the current understanding of the carcinogenicity of estrogens is based on clinical observations of a greater risk of endometrial hyperplasia and neoplasia associated with estrogen supplementation and experimental data. The following mechanisms are considered to be responsible for the carcinogenicity of estrogens: a receptor-mediated hormonal activity, which has generally been related to stimulation of cellular proliferation, resulting in more opportunities for accumulation of genetic damage leading to carcinogenesis; and, cytochrome P450-mediated metabolic activation, which elicits direct genotoxic effects by increasing mutation rates. There is also evidence that estrogen compromises the DNA repair system and allows the accumulation of lesions in the genome essential to estrogen-induced tumorigenesis. Disappointingly, the molecular mechanisms underlying each of these risk factors associated with development of breast cancer are not completely understood.
It is generally believed that initiation of breast carcinogenesis results from uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis, as a consequence of accumulative genetic damages that lead to activation of proto-oncogenes and inactivation of tumor suppressor genes. Genetic alterations can be either inherited as germline mutations or acquired as somatic mutations that occur as a result of exposure to environmental physical (e.g., excess ionizing radiation), chemical (e.g., carcinogens), and biological carcinogens (e.g., virus). The altered genotype of an initiated cell is irreversible, but the expression of transformed phenotypes requires further genetic or epigenetic changes. In the classical two-stage view of carcinogenesis that is primarily derived from animal models of chemical carcinogenesis, the second stage of tumorigenesis (i.e., promotion) involves epigenetic changes exclusively and is considered reversible.
Whether this is true in breast carcinogenesis remains to be determined, but it is safe to say that the model is oversimplified. Development of breast cancer entails multiple events, in which estrogen may play an important role. Furthermore, the relation between estrogen as an endogenous carcinogenic agent requires a reliable understanding of the normal breast under the influence of physiological conditions and of the pathogenetic pathway of preneoplastic lesions and cancer. In addition, an in vitro system of human breast epithelial cells that can reproduce the main steps of the in vivo situation such as cell immortalization and transformation, and the ability to manipulate the system for determining which of the genomic changes are important in the neoplastic process are needed. Therefore, it is predicted that an in vitro system of this nature will allow testing the hypothesis that estrogens are endogenous carcinogens either in the initiation or promotional phase of breast cancer. In this report we summarized our finding indicating the transforming effect of 17 beta estradiol and diethylstilbestrol in human breast epithelial cells (HBEC). The expression of phenotypes of cell transformation is associated with genomic changes that are detected using the technique of microsatellite DNA polymorphism and microarrays. Lastly, we have improved our technique of laser capture microscopy that will allow us to detect if the changes observed in vitro are also demonstrated in primary tumors and preneoplastic lesions of the breast.