Molecular and anatomic considerations in the pathogenesis of breast cancer

In spite of the recent recognition of specific genes associated with an ele vated lifetime incidence risk of breast cancer, the molecular mechanisms of breast tumor formation remain largely unknown. Tumorigenesis is thought to be highly complex, likely involving the accumulation of 5-10 genetic and e pigenetic events. Recent investigations have begun to identify some of thes e events, and in vitro model systems for breast tumorigenesis, including ra diation-induced breast cancer, are expected to provide further insight. Nor mal human breast epithelial cells exhibit a finite life span, both in vivo and in vitro. A critical event in oncogenic transformation is the ability o f cells to multiply indefinitely, a phenomenon referred to as "immortalizat ion." Using human papillomavirus (HPV) oncogenes, multiple normal breast ep ithelial subtypes have been shown to have distinct susceptibilities to immo rtalization by the HPV E6 and E7 oncogenes. Because HPV E6 and E7 inactivat e two well-known tumor suppressor proteins, p53 and Rb, respectively, this suggests that a cell-type-specific predominance exists with respect to thes e tumor suppressor pathways. Additional evidence for variability to oncogen ic stimuli among normal breast epithelial cells is provided by findings of locally confined loss of heterozygosity. An in vitro model of radiation-ind uced breast cancer is associated with early abrogation of p53 function. The resultant pair of normal and radiation-transformed breast epithelial cells serves as a useful system to identify other genes critically relevant to b reast tumorigenesis. These and other models should help further define the molecular mechanisms underlying the early steps of breast cancer formation. (C) 1999 Wiley-Liss, Inc.