Wazer D E, Band V
Department of Radiation Oncology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Radiat Oncol Investig. 1999;7(1):1-12. doi: 10.1002/(sici)1520-6823(1999)7:1<1::aid-roi1>3.0.co;2-i.
In spite of the recent recognition of specific genes associated with an elevated 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 epigenetic events. Recent investigations have begun to identify some of these events, and in vitro model systems for breast tumorigenesis, including radiation-induced breast cancer, are expected to provide further insight. Normal human breast epithelial cells exhibit a finite life span, both in vivo and in vitro. A critical event in oncogenic transformation is the ability of cells to multiply indefinitely, a phenomenon referred to as "immortalization." Using human papillomavirus (HPV) oncogenes, multiple normal breast epithelial subtypes have been shown to have distinct susceptibilities to immortalization by the HPV E6 and E7 oncogenes. Because HPV E6 and E7 inactivate two well-known tumor suppressor proteins, p53 and Rb, respectively, this suggests that a cell-type-specific predominance exists with respect to these tumor suppressor pathways. Additional evidence for variability to oncogenic stimuli among normal breast epithelial cells is provided by findings of locally confined loss of heterozygosity. An in vitro model of radiation-induced 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 breast tumorigenesis. These and other models should help further define the molecular mechanisms underlying the early steps of breast cancer formation.
尽管最近已认识到与乳腺癌终生发病风险升高相关的特定基因，但乳腺肿瘤形成的分子机制仍 largely 未知。肿瘤发生被认为是高度复杂的，可能涉及 5 - 10 个遗传和表观遗传事件的积累。最近的研究已开始识别其中一些事件，并且用于乳腺肿瘤发生的体外模型系统，包括辐射诱导的乳腺癌，有望提供进一步的见解。正常人类乳腺上皮细胞在体内和体外都表现出有限的寿命。致癌转化中的一个关键事件是细胞无限增殖的能力，这种现象称为“永生化”。使用人乳头瘤病毒（HPV）癌基因，已表明多种正常乳腺上皮亚型对 HPV E6 和 E7 癌基因的永生化具有不同的敏感性。由于 HPV E6 和 E7 分别使两种众所周知的肿瘤抑制蛋白 p53 和 Rb 失活，这表明在这些肿瘤抑制途径方面存在细胞类型特异性优势。正常乳腺上皮细胞中致癌刺激变异性的额外证据由局部受限的杂合性缺失的发现提供。辐射诱导的乳腺癌的体外模型与 p53 功能的早期废除有关。由此产生的一对正常和辐射转化的乳腺上皮细胞作为一个有用的系统，用于识别与乳腺肿瘤发生密切相关的其他基因。这些模型和其他模型应有助于进一步确定乳腺癌形成早期步骤背后的分子机制。
