Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture.
Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture.
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发表时间：
1988-01
期刊：
影响因子：
11.2
通讯作者：
B. Henderson;R. Ross;L. Bernstein
中科院分区：
文献类型：
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作者：
B. Henderson;R. Ross;L. Bernstein
Bittner 等人首先提出了激素可引起肿瘤（即增加肿瘤发生率）的概念。 (1)、基于雌激素与小鼠乳腺癌的实验研究。我们将这一概念提炼为雌激素和其他激素在几种人类癌症病因学中发挥主要作用的假设 (2)。该假说的一个关键要素是，肿瘤是特定靶器官过度激素刺激的结果，其正常生长和功能受到激素控制。该末端器官（例如子宫内膜、乳房）对激素增殖作用的反应是从正常生长到增生再到肿瘤的过程。在该模型中，在没有化学物质或电离辐射等外部引发剂的情况下，激素会增加肿瘤的发生率。我们假设了雌激素在激素诱发的肿瘤模型中发挥作用的三种特定情况。在与乳房和子宫内膜有关的前两种情况下，雌激素本身充当刺激激素，增加靶器官有丝分裂活动的频率。作为这种雌激素诱导的增殖的罕见后果，由于细胞分裂机制的错误（例如 DNA 复制错误、染色体易位等）而出现恶性表型（图 1）。我们认为，乳腺癌风险主要取决于乳腺组织对生物可利用雌激素的累积暴露总量以及相关的累积有丝分裂活性。尽管相关机制适用于子宫内膜癌，但子宫内膜中的关键暴露不是雌激素本身，而是不受孕激素改变影响的那部分雌激素。这两种雌激素诱发的肿瘤的主要预防可能不是通过控制传统的外源性引发剂的暴露，而是通过修改直接影响女性整个身体中雌激素本身的分泌、组织结合和可用性的因素。
The concept that hormones can cause, i.e., increase the incidence of, neoplasia was first developed by Bittner et al. (1), based on experimental studies of estrogens and mammary can cer in mice. We have refined that concept into a hypothesis for a major role of estrogen and other hormones in the etiology of several human cancers (2). A key element of this hypothesis is that neoplasia is the consequence of excessive hormonal stim ulation of a particular target organ, the normal growth and function of which are under hormonal control. The response of this end organ (e.g., endometrium, breast) to the proliferative effects of the hormone is a progression from normal growth to hyperplasia to neoplasia. In this model, hormones increase the incidence of neoplasia in the absence of outside initiators such as chemicals or ionizing radiation. We have hypothesized three specific circumstances in which estrogen plays a role in this model of hormone-induced neopla sia. In the first two circumstances, which relate to the breast and the endometrium, estrogens themselves act as the stimu latory hormones, increasing the frequency of mitotic activity in the target organ. As rare consequences of this estrogen-induced proliferation, malignant phenotypes develop due to errors in the mechanics of cell division (e.g., DNA copying errors, chro mosomal translocations, etc.) (Fig. 1). We believe that breast cancer risk is determined primarily by the total cumulative exposure of breast tissue to bioavailable estrogens and the associated cumulative mitotic activity. Al though a related mechanism applies to endometrial cancer, the critical exposure in the endometrium is not estrogen per se but that fraction of estrogen which is unopposed by the modifying influences of progesterone. The primary prevention of these two estrogen-induced neoplasms probably will come not from control of exposure to classical exogenous initiators but from modification of factors which directly affect the secretion, tissue binding, and availability of estrogen itself over a woman's entire