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.
Prolactin (PRL) is essential for a number of developmental events in the mammary gland. Work with PRL and PRL receptor knockout mice has shown that PRL indirectly regulates ductal side branching during puberty and directly controls lobuloalveolar development and lactogenesis during pregnancy. Anterior pituitary or placental PRL is thought to be responsible for these functions via an endocrine mechanism; however, PRL is also produced in a number of extrapituitary sites including the mammary gland. The physiologic relevance of mammary PRL remains unknown. In this study we utilized mammary recombination in Rag1(-/-) hosts, to determine whether mammary PRL plays a role in the regulation of mammary gland development. Mammary glands formed with the PRL gene deleted from either the epithelium, stroma, or both displayed normal development, on the basis of whole mount and hematoxylin and eosin histology, during puberty and lactation. At the end of pregnancy, a 2.8-fold decrease in bromodeoxyuridine incorporation was observed in the epithelial cells of mammary glands formed using PRL knockout epithelium compared with those formed using wildtype epithelium. No balancing alteration in the rates of apoptosis was detected. Thus, mammary-derived PRL influences mammary epithelial cell proliferation via an autocrine/paracrine mechanism, establishing a physiologic function for mammary PRL during mammopoiesis.
Prolactin (PRL) is necessary for the genesis of mammary alveolar buds and for lactation. A cDNA library enriched for PRL-dependent genes was made by suppression subtractive hybridization. Aldolase C/zebrin (AldC/zebrin), a brain-specific aldolase, was found to be PRL-dependent in the mouse mammary glands. AldC/zebrin was preferentially expressed in the alveolar buds. Expression of the gene in the ovary was also evident. During pregnancy, mammary AldC/zebrin mRNA levels were elevated beginning at midpregnancy (d 10 of pregnancy) in accordance with the genesis of the lobuloalveolar system, and the expression level was gradually increased through the end of pregnancy. Lactating mammary gland contained a very high level of AldC/zebrin mRNA, and the gene expression decreased during involution. By contrast, levels of aldolase A and B mRNA expression in the mammary glands were less affected by pregnancy and lactation. The selective regulation of AldC/zebrin may contribute to a shift in nutrient metabolism during pregnancy and lactation to facilitate epithelial growth and biosynthesis of milk constituents.
Glycosylation-dependent cell adhesion molecule 1 (GlyCAM 1), a mucin-like endothelial glycoprotein, was induced by PRL and suppressed by progesterone in the mammary gland of mice, and in HC11 mouse mammary epithelial cells. Complementary DNA microarray analysis revealed that expression of GlyCAM 1 was reduced in the mammary gland of PRL-gene disrupted mice (PRL-/-) compared with control (PRL+/-) littermates. This result was confirmed by in situ hybridization and immunostaining. The messenger RNA (mRNA) encoding GlyCAM 1 was present in mammary epithelia of PRL-stimulated mice. Immunohistochemistry indicated that GlyCAM 1 protein was detectable both in mammary epithelia and in the ductal lumen in PRL+/- virgin mice, but not in PRL-/- mice. GlyCAM 1 mRNA was highly induced by grafting pituitary glands from normal littermates. Trace amounts of mRNA for GlyCAM 1 were detected by RT-PCR in mammary tissue of PRL-/- mice. Progesterone inhibited both basal and PRL-stimulated GlyCAM 1 transcription. In HC11 cells, GlyCAM 1 mRNA was induced in cells treated with insulin, dexamethasone, and PRL. Similar to the in vivo studies, progesterone inhibited the induction of GlyCAM 1 transcription. In CHO cells, PRL stimulated transcription of a luciferase reporter gene containing an 800-bp promoter fragment of GlyCAM 1, and progesterone partially suppressed the PRL effect. These data demonstrate that expression of GlyCAM 1 in mammary gland is under the control of both PRL and progesterone.
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