The incidence of cervical adenocarcinomas in young women over the last two decades has increased. Even with increasing knowledge of the role of human papillomavirus in the etiology of adenocarcinoma of the cervix, there is a paucity of data concerning the genetic and epigenetic factors that contribute to the histologic features and biologic behaviors of these tumors. Lactoferrin is a basic glycoprotein found in human milk, secondary granules of neutrophils, and many body secretions, and it has been associated with carcinogenesis of the endometrium, breast, and lymphoid systems. In this study, we examined the expression of lactoferrin in normal human endocervical epithelium and in cervical adenocarcinomas in relation to proliferative index, steroid receptor status, p53 protein expression, and apoptosis. Immunohistochemical and in situ studies demonstrated that lactoferrin protein and mRNA were strikingly downregulated upon neoplastic transformation of the endocervix as early as in adenocarcinoma in situ when compared with the prominent expression exhibited by the normal cervical epithelium. Furthermore, neoplastic transformation of endocervical epithelial cells was accompanied by a pronounced stimulation of proliferation and a substantial reduction in the expression of the estrogen and progesterone receptors and p53 but little or no change in the number of apoptotic cells. In conclusion, we identified lactoferrin as a novel cancer-specific marker of endocervical adenocarcinomas that may be useful in the early detection of the disease, prediction of prognosis, and the development of new therapeutic modalities.
The effects of estradiol-17Β (E2) and clomiphene citrate (CC) on pituitary-uterine function in ovariectomized (OVX) rats were compared in two experiments. In experiment 1 CC completely blocked E2 stimulation of uterine weight when administered concurrently for 10 and 30 days. In experiment 2, content of total (occupied and unoccupied) uterine nuclear estrogen receptors was increased by E2, but not by CC, compared to OVX controls. Only a fraction of the nuclear receptors was occupied in E2-treated rats, whereas all of these receptor sites were occupied in CC-treated rats. In addition, uterine cytoplasmic estrogen receptors were increased by E2 and diminished by CC treatment. Both E2 and CC were effective in preventing the postovariectomy rise in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), although LH was always inhibited to a greater extent than FSH. After 30 days of treatment, pituitary gonadotropins were also substantially reduced by E2 and CC, suggesting that long-term treatment decreased both pituitary synthesis and release. An increase in pituitary weight observed in E2-treated rats only was due largely to the stimulation of lactotropes, as serum prolactin was increased. In summary, although CC and E2 similarly depressed pituitary gonadotropin secretion, they exhibited marked differences in the stimulation and occupancy of uterine estrogen receptors and the stimulation of pituitary prolactin secretion.
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