Closure of the tight junctions of the mammary epithelium has been shown to accompany the onset of copious milk secretion or lactogenesis, stage 2, in both goats and humans. Here we use injection of [ 14 C]sucrose and FITC-albumin (fluorescein isothiocyanate-albumin) into the mammary duct to follow the course of tight junction closure during lactogenesis in mice. To examine the hormonal changes responsible, we ovariectomized day 16 or 17 pregnant mice and found that closure followed ovariectomy with a mean delay of 13·6 1·5 (...) h. That progesterone withdrawal is the trigger for closure was shown by the finding that injection of progesterone within 4 h of ovariectomy delayed closure and that closure occurred after injection of the progesterone antagonist RU 486 in intact late pregnant mice. Endocrine ablation studies showed that low to moderate concentrations of corticosterone and either placental lactogen or prolactin are necessary for tight junction closure triggered by progesterone withdrawal. Thus the hormonal requirements for tight junction closure are similar to those shown by other investigators to promote lactogenesis, stage 2. Further, the tight temporal control of tight junction permeability suggests that ovariectomy of the late pregnant mouse may be a good model for molecular studies of the lactogenic switch.
Experimental testing of growth, metastatic progression and drug responsiveness of human breast cancer in vivo is performed in immunodeficient mice. Drug candidates need to show promise against human breast cancer in mice before being allowed into clinical trials. Breast cancer growth is under endocrine control by ovarian steroids and the pituitary peptide hormone prolactin. While it is recognized that the most relevant biologic effects of prolactin are achieved with prolactin from the matching species, the biologic efficacy of mouse prolactin for human prolactin receptors has not been recorded. Thus, it is unclear whether the mouse endocrine environment adequately reflects the hormonal environment in breast cancer patients with regard to prolactin. We now show both recombinant and natural pituitary-derived mouse prolactin to be a poor agonist for human prolactin receptors. Mouse prolactin failed to induce human prolactin receptor-mediated biologic responses of cell clustering, proliferation, gene induction and signal transduction, including activation of Stat5, Stat3, Erk1/2 and Akt pathways. Consistent data were derived from human breast cancer lines T-47D, MCF-7 and ZR-75·1, as well as human prolactin receptor-transfected COS-7 and 32D cells. Failure of mouse prolactin to activate human prolactin receptors uncovers a key deficiency of the mouse endocrine environment for human xenotransplant studies. Since most human breast cancers express prolactin receptors, human breast cancer transferred into mice is unnaturally selected for growth in the absence of circulating prolactin. The new insight raises concerns about the validity of analyzing biology and drug responsiveness of human breast cancer in existing mouse xenotransplant models.
Consecutive daily serum samples were obtained over 25–30 days from 2 pre-pubertal girls (Stage I), 2 girls with breast development alone (Stage II); one girl with both breast development and pubic hair (Stage III), and 2 girls who were six months and three years post-menarche, respectively (Stage IV). All serum samples were assayed for LH, FSH, progesterone and 17-hydroxyprogesterone. Sera from 6 girls were assayed for testosterone, and sera from 3 were assayed for oestradiol.
The patterns of gonadotrophins and sex steroid concentrations in both Stage I and Stage II girls were characterized by day to day stability. LH and FSH concentration was increased in Stage II subjects, while steroid concentration were similar to those in Stage I. The Stage III subject showed marked, apparently random, fluctuations in the concentrations of LH, FSH, oestradiol and 17-hydroxyprogesterone. In Stage IV, as early as six months post-menarche, there was a definite peak in the serum concentration of gonadotrophins, 17-hydroxyprogesterone and oestradiol. However, luteal phase length and maximal progesterone levels of these post-menarchial girls were less than those observed for normal adult females.
These data are consistent with evolution of the adult menstrual pattern of hormone secretion through a series of developmental stages.
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