Spady T J, Pennington K L, McComb R D, Shull J D
Eppley Institute for Research in Cancer, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha 68198-6805, USA.
Endocrinology. 1999 Jun;140(6):2828-35. doi: 10.1210/endo.140.6.6757.
Estrogens stimulate cell proliferation in a variety of tissues and are widely believed to be contributing factors in the etiology of certain cancer types in humans. The molecular mechanisms through which estrogens regulate cell proliferation are currently unknown. Estrogens stimulate proliferation of the PRL-producing lactotroph of the rat anterior pituitary gland and induce development of PRL-producing pituitary tumors in several inbred rat strains. Therefore, the lactotroph provides a well defined model for identifying the mechanisms through which estrogens regulate cell proliferation and/or survival. Data from our laboratory and others indicate that the relative sensitivity to the pituitary growth-promoting actions of estrogens is highly strain specific. This allows genetics-based approaches to be used to address the molecular mechanisms through which estrogens stimulate lactotroph proliferation and induce pituitary tumor development. In the present study we have examined the ability of diethylstilbestrol (DES) to induce pituitary growth in the genetically related AxC-Irish (ACI) and Copenhagen (COP) strains and their derived F1, F2, and backcross progeny. The data presented herein indicate that the anterior pituitary gland of the ACI strain displays approximately a 2-fold greater growth response to administered DES than does the pituitary gland of the COP strain. The average pituitary weight in male ACI rats was increased from 9.2 +/- 0.2 mg (mean +/- SD in untreated rats to 63.7 +/- 12.6 mg in rats treated with DES for 12 weeks, whereas in male COP rats, DES increased pituitary weight from 12.7 +/- 0.9 to 38.1 +/- 8.2 mg. The ACI phenotype was inherited in the F1, F2, and backcross progeny of an ACI x COP intercross as a dominant genetic trait, and the approximately 30 mg of additional pituitary growth displayed by the DES-treated ACI rat, relative to that of the treated COP rat, appeared to result from the actions of a single locus. Moreover, in F1 progeny from an ACI x Brown Norway intercross, the ACI phenotype was inherited as a dominant or incompletely dominant genetic trait. These data, when compared with findings of previous studies using the Fischer 344 rat strain, provide the first indication that distinct genetic pathways contribute to regulation of estrogen-induced pituitary growth and induction of PRL-producing pituitary tumors in the ACI and F344 rat strains.
雌激素可刺激多种组织中的细胞增殖，人们普遍认为它是人类某些癌症类型病因中的一个促成因素。目前尚不清楚雌激素调节细胞增殖的分子机制。雌激素可刺激大鼠垂体前叶分泌催乳素的泌乳细胞增殖，并在几种近交系大鼠中诱发分泌催乳素的垂体肿瘤。因此，泌乳细胞为确定雌激素调节细胞增殖和/或存活的机制提供了一个明确的模型。我们实验室和其他机构的数据表明，对雌激素促进垂体生长作用的相对敏感性具有高度的品系特异性。这使得基于遗传学的方法可用于研究雌激素刺激泌乳细胞增殖和诱发垂体肿瘤发生的分子机制。在本研究中，我们检测了己烯雌酚（DES）诱导遗传相关的AxC-爱尔兰（ACI）和哥本哈根（COP）品系及其衍生的F1、F2和回交后代垂体生长的能力。本文提供的数据表明，与COP品系的垂体相比，ACI品系的垂体前叶对给予的DES表现出约2倍的更大生长反应。雄性ACI大鼠的垂体平均重量从9.2±0.2毫克（未处理大鼠的平均值±标准差）增加到用DES处理12周的大鼠的63.7±12.6毫克，而在雄性COP大鼠中，DES使垂体重量从12.7±0.9增加到38.1±8.2毫克。ACI表型在ACI×COP杂交的F1、F2和回交后代中作为显性遗传性状遗传，相对于经处理的COP大鼠，经DES处理的ACI大鼠额外显示出约30毫克的垂体生长似乎是由单个基因座的作用导致的。此外，在ACI×挪威棕杂交的F1后代中，ACI表型作为显性或不完全显性遗传性状遗传。与之前使用Fischer 344大鼠品系的研究结果相比，这些数据首次表明不同的遗传途径有助于调节雌激素诱导的垂体生长以及ACI和F344大鼠品系中分泌催乳素的垂体肿瘤的诱导。
