Adami H O, Persson I, Ekbom A, Wolk A, Pontén J, Trichopoulos D
Department of Cancer Epidemiology, Uppsala University Hospital, Sweden.
Mutat Res. 1995 Dec;333(1-2):29-35. doi: 10.1016/0027-5107(95)00128-x.
Whilst investigators have clearly shown that non-hereditary factors dominate the aetiology of human breast cancer, they have failed to identify quantitatively important causes, and prospects for prevention remain indeed limited. However, progress in epidemiological and basic research has taken place during the last few years. Current evidence suggests that breast cancer may be affected by the intra-uterine environment, that exposures during adolescence are particularly important, and that pregnancy has a dual effect on breast cancer risk: an early increase followed by long-term protection. Great variation exists in the structural development of the breast ductal system already in the newborn--and by inference in utero--and a pregnancy induces permanent structural changes in the mammary gland. We suggest that these observations fit into an aetiological model with the following key components: (1) breast cancer risk depends on the number of cells at risk, the susceptibility of individual cells to malignant transformation, and on the degree of cellular proliferation, notably cells which can act as founders of breast cancer; (2) the number of target cells is determined by the hormonal environment mainly early in life, perhaps already in utero; (3) in adult life, hormones which are non-genotoxic, increase breast cancer risk by increasing selective cell proliferation and thus number of target cells and the risk of retention of spontaneous somatic mutations; (4) while a pregnancy stimulates the growth of already malignant cells or cells close to malignant transformation (and thereby entails a short-term risk increase) the dominating long-term protection occurs due to permanent structural changes, terminal differentiation and perhaps decreased cell proliferation and carcinogen-binding in combination.
虽然研究人员已明确表明非遗传因素在人类乳腺癌病因中占主导地位，但他们未能确定在数量上具有重要意义的病因，预防前景确实仍然有限。然而，在过去几年中，流行病学和基础研究取得了进展。目前的证据表明，乳腺癌可能受子宫内环境影响，青春期的暴露尤为重要，而且怀孕对乳腺癌风险有双重影响：早期风险增加，随后是长期保护。新生儿期乳腺导管系统的结构发育就已存在很大差异——由此推断在子宫内时也是如此——而怀孕会引起乳腺的永久性结构变化。我们认为，这些观察结果符合一个病因模型，该模型具有以下关键要素：（1）乳腺癌风险取决于处于风险中的细胞数量、单个细胞对恶性转化的易感性以及细胞增殖程度，特别是那些可作为乳腺癌起始细胞的细胞；（2）靶细胞数量主要由生命早期、或许在子宫内时的激素环境决定；（3）在成年期，非基因毒性激素通过增加选择性细胞增殖从而增加靶细胞数量以及自发体细胞突变保留的风险来增加乳腺癌风险；（4）虽然怀孕会刺激已恶变细胞或接近恶性转化细胞的生长（从而带来短期风险增加），但主要的长期保护作用是由于永久性结构变化、终末分化以及可能是细胞增殖减少和致癌物结合减少共同作用的结果。
