Mammary gland development is controlled by a dynamic interplay between endocrine hormones and locally produced factors. Biogenic monoamines (serotonin, dopamine, norepinephrine, and others) are an important class of bioregulatory molecules that have not been shown to participate in mammary development. Here we show that mammary glands stimulated by prolactin (PRL) express genes essential for serotonin biosynthesis (tryptophan hydroxylase [TPH] and aromatic amine decarboxylase). TPH mRNA was elevated during pregnancy and lactation, and serotonin was detected in the mammary epithelium and in milk. TPH was induced by PRL in mammosphere cultures and by milk stasis in nursing dams, suggesting that the gene is controlled by milk filling in the alveoli. Serotonin suppressed beta-casein gene expression and caused shrinkage of mammary alveoli. Conversely, TPH1 gene disruption or antiserotonergic drugs resulted in enhanced secretory features and alveolar dilation. Thus, autocrine-paracrine serotonin signaling is an important regulator of mammary homeostasis and early involution.

Homeostatic control of volume within the alveolar spaces of the mammary gland has been proposed to involve a feedback system mediated by serotonin signaling. In this article, we describe some of the mechanisms underlying this feedback based on studies of a human normal mammary epithelial cell line (MCF10A) and mouse mammary epithelium. Mammary serotonin was elevated during lactation and after injection of 5-hydroxytryptophan (5-HTP). The genes encoding the serotonin reuptake transporter (SERT) and the type 7 serotonin receptor (5-HT 7) were expressed in human and mouse mammary epithelial cells, and serotonin caused a concentration-dependent increase of cAMP in MCF10A cells. Mouse and human mammary epithelial cells formed polarized membranes, in which tight junction activity was monitored. Treatment of mammary epithelial membranes with serotonin receptor antagonists increased their transepithelial electrical resistance (TEER). Antagonist and agonist effects on TEER were mediated by receptors on the basolateral face of the membranes. Our results suggest a process in which serotonin accumulates in the interstitial fluid surrounding the mammary secretory epithelium and is detected by 5-HT7 receptors, whereupon milk secretion is inhibited. One mechanism responsible for this process is serotonin-mediated opening of tight junctions, which dissipates the transepithelial gradients necessary for milk secretion.lactation ͉ MCF10A ͉ milk protein ͉ serotonin receptor ͉ serotonin transporter

Male (1--60 days old) and female (1--30 days old) hamsters were decapitated and serum levels of LH, FSH, PRL, progesterone, androgens (males), and estradiol (females) were measured by RIA. Males and females had similar levels of LH until 15 days of age and of FSH until 12 days of age, at which times gonadotropin levels increased significantly in females. Peak levels for females occurred on days 19--21 for LH and on days -2--24 for FSH, later than the times reported for female rats. Adjusting female gonadotropin peaks for gestation length places these peaks for hamsters and rats at the same time in postmating age. In female hamsters, large variations occur in LH between 16--25 days of age, as reported for female rats. Males reached peak serum levels of LH and FSH on day 40, just before the first motile epididymal sperm. Serum PRL levels were identical in male and female hamsters until at least day 30. PRL levels sharply increased in both sexes after day 18 and remained elevated until at least day 30. In males, serum androgens were low until 30 days of age, in contrast to high levels reported for infantile rats. Androgens rose sharply in male hamsters after day 30 to peak levels on day 50. Progesterone in males also remained low until after day 30. Serum estradiol in females did not attain the extremely high elevations seen in rats. Some fluctuations occurred between 10--30 days of age, which presumably represent maturational changes in the ovary. Serum progesterone in females followed a pattern of development similar to estradiol.

Prolactin (PRL), interacting with other hormones from the pituitary, gonad, and placenta, activates speci®c signals that drive the appropriately timed morphological and functional development of the mammary gland. A mouse model of isolated PRL de®ciency (PRL 7/7 ) was created by gene disruption in an e ort to further understand the molecular basis of mammary gland development and breast cancer. Whereas primary ductal growth was normal in PRL 7/7 mice, ductal arborization was minimal (branches/mm 2 =1.5+0.5), and lobular budding was absent. Replacement therapy with PRL injections stimulated a modest degree of lobular budding and ductal arborization (3.75+0.9). Pituitary transplants to the kidney capsule of PRL 7/7 mice restored lobular budding and ductal arborization, to the full extent of that seen in control animals (20.3+5.5). Pregnancy, established by mating progesterone-treated PRL 7/7 females with PRL 7/7 males, led to complete morphological development of the mammary gland, appropriate to the gestational stage. PRL treatment stimulated tyrosine phosphorylation and DNA binding activity of Stat5a, but not Stat1 in PRL 7/7 or PRL +/7 females, and Stat5a, but not Stat1, was elevated by estradiol within 24 h. PRL-de®cient mice were crossed with mice expressing a dominant oncogene (polyoma middle-T antigen driven by the MMTV promoter, PyVT mice). Palpable (1 mm 3 ) tumors were detected an average of 9 days earlier in hormonally normal females (PRL +/7 :PyVT) compared with littermates that were PRL-de®cient (PRL 7/7 :PyVT). The growth rate of PyVT-induced tumors was 30% faster in PRL +/7 , than in PRL 7/7 females.