We have demonstrated and localized human GH (hGH) gene expression in surgical specimens of normal human mammary gland and in proliferative disorders of the mammary gland of increasing severity using sensitive in situ RT-PCR methodology. hGH mRNA identical to pituitary hGH mRNA was first detected by RT-PCR of RNA derived from samples of normal human mammary gland. Cellular localization of hGH gene expression in the normal mammary gland exhibited restriction to luminal epithelial and myoepithelial cells of the ducts and to scattered stromal fibroblasts. We subsequently examined the expression of the hgh gene in three progressive proliferative disorders of the human mammary gland, i.e. A benign lesion (fibroadenoma), a pre-invasive stage (intraductal carcinoma) and an invasive ductal carcinoma. hGH mRNA was readily detected in the tumoral and non-tumoral epithelial components and also in cells of the reactive stroma including fibroblasts, myofibroblastic and myoepithelial cells, inflammatory infiltrate lymphocytes and endothelial cells in areas of neovascularization. In all three proliferative disorders examined, the intensity of the cellular labeling observed in both the epithelial and stromal compartments was always stronger compared with that in adjacent normal tissue. hGH protein was also present in significantly higher concentration in extracts derived from proliferative disorders of the mammary gland compared with extracts derived from normal mammary gland. We also examined hGH gene expression in axillary lymph nodes not containing and containing metastatic mammary carcinoma. hGH gene expression was evidenced in metastatic mammary carcinoma cells and in reactive stromal cells by both in situ hybridization and in situ RT-PCR. In contrast, in lymph nodes not containing metastatic mammary carcinoma, hGH mRNA was detected only by use of in situ RT-PCR. Thus, increased expression of the hGH gene in the epithelial component and the de novo stromal expression in proliferative disorders of the mammary gland are suggestive of a pivotal role for autocrine hGH in neoplastic progression of the mammary gland.
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M Raccurt, PE Lobie, E Moudilou, T Garcia-Caballero, L Frappart, G Morel, and HC Mertani
P.D. Gluckman, P.C.H. Morel, G.R. Ambler, B.H. Breier, H.T. Blair, and S.N. McCutcheon
Fetal growth is normally constrained by maternal factors. This constraint is demonstrated by the usual inverse linear relationship between litter size and mean fetal weight. Cross-breeding experiments between mice of lines selected for high or low plasma insulin-like growth factor (IGF-I) levels suggested that elevations in maternal IGF-I abolish (P <0.01) this constraining effect and reverse the usual positive relationship between fetal and placental size in late gestation. This was confirmed by treating mice and rats throughout pregnancy with IGF-I. In normal mice and in low IGF-I line mice treatment with IGF-I 10μg 8-hourly s.c. from day 1 to 19 of pregnancy) abolished maternal constraint whereas 0.9% (w/v) NaCl treatment did not. In Wistar rats osmotic pumps were implanted to deliver IGF-I (1μg/g body weight per day), bovine GH (bGH; 0.6μg/g body weight per day) or saline from day 1 to 19 of pregnancy. IGF-I therapy but not bGH or saline abolished (P < 0.01) maternal constraint and altered (P <0.01) the relationship between placental and fetal weight.
When high or low IGF-I line mice embryos were transplanted into a normal line of mice, the expected negative relationship (P <0.05) between mean fetal weight and litter size was maintained. However the embryos of the high line were heavier (P <0.05) than those from the low line irrespective of fetal number, suggesting a direct role for IGF-I in the regulation of fetal growth.
Thus both endogenous and exogenous elevations in maternal IGF-I indirectly promote fetal growth either by altering nutrient delivery to the placenta or by affecting placental function.