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首页> 美国卫生研究院文献>Endocrine Reviews >Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions
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Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions

机译：从正常乳腺发育到肿瘤前乳腺病变的生长激素和类胰岛素生长因子-I

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Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations.
机译：成年女性的乳腺发育始于青春期，并受一组激素和生长因子之间严格调控的串扰控制。尽管雌激素是最初的驱动力，并与黄体期孕酮结合，但这两种激素均需要乳腺中GH诱导的IGF-I才能起作用。同一组荷尔蒙在实验上受到干扰时，可能导致增生性病变的发展，并增加乳腺癌的机会或成为其前兆。例如，GH或IGF-I的全身性给药引起乳腺增生，而转基因动物中IGF-I的过量产生可引起普通或非典型增生的发展，有时还导致癌变。尽管研究已经清楚地证明了GH和IGF-I受体在细胞培养和动物中的转化潜力，但关于它们在体内癌症发展中的主要作用实际上是指导性的还是允许性的，仍存在争议。已经显示出遗传印记最早出现在女性的非典型增生中。因此，通过上述对激素和生长因子敏感的前体病变从正常发展到癌症的进展概念在人以及动物模型中都得到了支持。实际上，在进展过程中雌激素受体，GH，IGF-I和IGF-I受体的升高提示了这些途径在该过程中的作用。靶向GH / IGF-1轴的新药物可能提供一种阻止前体病变形成和发展为明显癌的新手段。最近已显示出一种新颖的生长抑素类似物，可通过对乳腺的IGF-I抑制作用来阻止大鼠乳腺发育。类似地，pegvisomant，GH拮抗剂和其他IGF-1拮抗剂（例如IGF结合蛋白1和5）也可阻断乳腺发育。因此，有可能通过抑制雌激素和孕激素的作用，尤其是在极有可能患乳腺癌的妇女中，抑制乳腺中的IGF-I作用或GH可能最终在乳腺癌的化学预防中发挥作用。癌症，例如BRCA基因1或2突变。

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