Mol J A, van Garderen E, Rutteman G R, Rijnberk A
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
J Steroid Biochem Mol Biol. 1996 Jan;57(1-2):67-71. doi: 10.1016/0960-0760(95)00251-0.
In contrast to the protective, anti-proliferative, action of progestins on the development of endometrium cancer, progestins may have local stimulatory and inhibitory effects on the proliferation of mammary epithelium. Until now there was no final molecular explanation of this discrepancy. Prolonged treatment of dogs with depot medroxyprogesterone acetate (DPMA) or with proligestone (PROL) results in enhanced plasma concentrations of growth hormone (GH), insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins, together with the development of benign mammary tumours. The stimulated plasma GH levels do not have the typical pulsatile secretion pattern, and are not sensitive to stimulation with GHRH or to inhibition with somatostatin. The autonomous secretion can be inhibited by the anti-progestin RUU-486. The source of progestin-induced plasma GH levels has been demonstrated to be the canine mammary gland where progestins induce the expression of the gene encoding GH. The expression of the GH gene is restricted to focal areas of hyperplastic epithelium as shown by immunohistochemistry, and is predominantly located in single positive epithelial cells with an intermediate position between luminal- and myo-epithelium. Progestin-induced fibroadenomatous changes in the mammary gland of cats are also associated with locally enhanced GH expression. In both normal, benign and malignant mammary tumours of humans GH mRNA expression has been demonstrated by RT-PCR. The presence of GH mRNA is associated with the presence of immunoreactive GH as shown by immunohistochemistry. Sequence analysis revealed 100% homology to the pituitary expressed GH gene. In malignant mammary tumours of humans and dogs GH expression is also found in specimens negative for progesterone receptors as measured by ligand binding. It is concluded that the gene encoding GH is expressed in the mammary gland of a variety of species, including man. This appears to represent a contribution to the molecular explanation of the action of progestins on proliferation of mammary epithelium. It needs, however, to be proven whether this local biosynthesis of GH in the mammary gland is the cause of the local stimulatory effect of progestins on the proliferation of mammary epithelium.
与孕激素对子宫内膜癌发展的保护、抗增殖作用相反，孕激素可能对乳腺上皮细胞的增殖具有局部刺激和抑制作用。到目前为止，对于这种差异尚无最终的分子解释。用醋酸甲羟孕酮长效注射剂（DPMA）或炔诺孕酮（PROL）对犬进行长期治疗，会导致生长激素（GH）、胰岛素样生长因子（IGF）-I、IGF-II和IGF结合蛋白的血浆浓度升高，同时会出现良性乳腺肿瘤。受刺激的血浆GH水平不具有典型的脉冲式分泌模式，并且对生长激素释放激素（GHRH）的刺激或生长抑素的抑制不敏感。抗孕激素RU486可抑制自主分泌。已证明孕激素诱导的血浆GH水平的来源是犬乳腺，在该部位孕激素可诱导编码GH的基因表达。免疫组织化学显示，GH基因的表达局限于增生上皮的局灶区域，主要位于腔上皮和肌上皮之间中间位置的单个阳性上皮细胞中。孕激素诱导的猫乳腺纤维腺瘤样改变也与局部GH表达增强有关。通过逆转录聚合酶链反应（RT-PCR）已证明在人类的正常、良性和恶性乳腺肿瘤中均有GH mRNA表达。免疫组织化学显示，GH mRNA的存在与免疫反应性GH的存在相关。序列分析显示与垂体表达的GH基因具有100%的同源性。在人类和犬的恶性乳腺肿瘤中，通过配体结合测量发现，在孕激素受体阴性的标本中也存在GH表达。得出的结论是，编码GH的基因在包括人类在内的多种物种的乳腺中表达。这似乎为孕激素对乳腺上皮细胞增殖作用的分子解释提供了依据。然而，尚需证实乳腺中GH的这种局部生物合成是否是孕激素对乳腺上皮细胞增殖产生局部刺激作用的原因。
