Chromosomal Instability: A New Paradigm for Estrogen-induced Oncogenesis

Human sporadic breast cancer (BC) comprises >90% of all BC cases whereas familial BC is less than 10% (1). Despite its likely multifactorial origin, there is now pervasive evidence fi-om epidemiological and animal studies, developed over the past several decades, that the causation of human sporadic BC primarily involves female sex hormones, particularly estrogens (Es) (1-8). This view is consistent with long standing epidemiological data relating extended exposure to Es and elevated BC risk, such as early first menarche, late age at menopause, nulliparity, late age at fill-term pregnancy, and absence of lactation (5,6). These BC risk factors are all related to pre-menopausal women. Moreover, all ofthe wellestablished BC risk factors are associated with elevated circulating E levels. Even lesser risk factors such as, obesity and alcohol ingestion are known to significantly increase serum E concentrations in women (9, 10). These earlier studies are buttressed by results of the recent Breast Cancer Prevention Trial in which tamoxifen (TAM) treatment markedly reduced (44-55%) BC risk in women considered at increased risk for the disease (1 1). Since it is evident that Es are crucial to our understanding of sporadic BC etiology, it is surprising that so little is known about the involvement of Es in oncogenic processes in target tissues such as the breast, other than its ability to elicit cell proliferation. Our laboratory has utilized two seemingly disparate animal models in which malignant tumors are induced solely by Es in the absence of any other exogenous intervening carcinogenic or promotional agent (12-15). Based on our recent findings, it has been concluded that the early detection of chromosomal instability (CIN) and aneuploidy, in early lesions and primary neoplasms in both systems, is a hallmark characteristic of E-induced oncogenesis.