Li Jonathan J, Li Sara Antonia
Division of Etiology & Prevention of Hormonal Cancers, and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA.
Adv Exp Med Biol. 2003;532:195-207. doi: 10.1007/978-1-4615-0081-0_15.
Estrogens are intimately involved in the causation of some of the most prevalent cancers afflicting women, particularly, breast, endometrial, cervico-vaginal, and possibly ovarian. Therefore, it has become particularly pertinent to elucidate the molecular changes and mechanisms whereby estrogens elicit their oncogenic actions so that better prevention strategies can be developed. The estrogen-induced Syrian hamster tumors of the kidney have emerged as one of the most intensively studied in-vivo models in solely estrogen-induced oncogenesis. An advantage of this model is that the tumors occur in the absence of any intervening morphologic changes, but rather they are the result of the continuous progression of a subset of interstitial stem cells in the kidney leading to tumor formation. Evidence is presented that the origin of these tumors is derived from ectopic "uterine" stem cells, which are responsive to estrogenic hormones. The other animal tumor model studied is the highly sensitive estrogen-induced mammary tumors of female ACI rats. Their steroid receptor and other gene alterations have been delineated. Importantly, a crucial early event in this solely estrogen-induced oncogenic process, common to both animal tumor models, is the overexpression and amplification of c-myc and its protein product. Chromosomal instability, in both early and large well-established frank tumors, is another important characteristic found during early E-induced oncogenesis. These features have been shown to be characteristic of human ductal carcinomas in-situ and in primary invasive ductal breast carcinomas. The molecular alterations seen are considered crucial in eliciting estrogen-induced oncogenesis and have established for the first time a direct causal link between estrogen and the induction of chromosomal instability and aneuploidy in these estrogen-associated neoplasms.
雌激素与一些女性常见癌症的发生密切相关，尤其是乳腺癌、子宫内膜癌、宫颈 - 阴道癌，可能还包括卵巢癌。因此，阐明雌激素引发致癌作用的分子变化和机制变得尤为重要，以便制定更好的预防策略。雌激素诱导的叙利亚仓鼠肾肿瘤已成为仅由雌激素诱导致癌作用中研究最深入的体内模型之一。该模型的一个优点是肿瘤在没有任何中间形态变化的情况下发生，相反，它们是肾脏间质干细胞亚群持续进展导致肿瘤形成的结果。有证据表明这些肿瘤起源于异位的“子宫”干细胞，它们对雌激素有反应。研究的另一种动物肿瘤模型是雌性 ACI 大鼠对雌激素高度敏感的乳腺肿瘤。其类固醇受体和其他基因改变已被阐明。重要的是，在这两种动物肿瘤模型共有的仅由雌激素诱导的致癌过程中，一个关键的早期事件是 c-myc 及其蛋白质产物的过表达和扩增。在早期和已形成的大型明显肿瘤中，染色体不稳定性是早期雌激素诱导致癌过程中发现的另一个重要特征。这些特征已被证明是人类导管原位癌和原发性浸润性导管乳腺癌的特征。所观察到的分子改变被认为在引发雌激素诱导的致癌作用中至关重要，并首次在这些雌激素相关肿瘤中建立了雌激素与染色体不稳定和非整倍体诱导之间的直接因果联系。
