+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects



Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects



Developmental Biology 229(1): 163-175



Prolactin (Prl)-induced phosphorylation of Stat (signal transducer and activator of transcription) 5 is considered a key event in functional mammary development and differentiation. We now demonstrate that not only Prl, but also growth hormone (GH) and epidermal growth factor (EGF), can activate Stat5 in mammary tissue. We investigated the roles of these hormones in mammary development using mice in which the respective receptors had been inactivated. Although Prl receptor (PrlR)-null mice are infertile, we were able to maintain pregnancies in a few mice by treatment with progesterone. Mammary tissue in these mice was severely underdeveloped and exhibited limited differentiation as assessed by the phosphorylation status of Stat5 and the expression of milk protein genes. PrlR +/- mice showed impaired mammary development and alveolar differentiation during pregnancy, which corresponded with reduced phosphorylation levels of Stat5a and 5b, and impaired expression of milk protein genes. Development of the glands in these mice was arrested at around day 13 of pregnancy. While Prl activated Stat5 only in the epithelium, GH and EGF activated Stat5 preferentially in the stroma. To assess the relevance of the GH receptor (GHR) in the mammary gland, we transplanted GHR-null epithelium into cleared fat pads of wild-type mice. These experiments demonstrated that the GHR in the epithelium is not required for functional mammary development. Similarly, the EGFR in the epithelium is not required for alveolar development. In contrast, epithelial PrlR is required for mammary development and milk protein gene expression during pregnancy. Although GH is not required for alveolar development, we were able to demonstrate its lactogenic function in cultured mammary epithelium from PrlR-null mice. However, ductal development in GHR-null mice was impaired, supporting the notion that GH signals through the stromal compartment. Our findings demonstrate that GH, Prl, and EGF activate Stat5 in separate compartments, which in turn reflects their specific roles in ductal and alveolar development and differentiation.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 003536064

Download citation: RISBibTeXText

PMID: 11133161

DOI: 10.1006/dbio.2000.9961


Related references

Prolactin, epidermal growth factor or transforming growth factor-alpha activate a mammary cell-specific enhancer in mouse mammary tumor virus-long terminal repeat. Molecular and Cellular Endocrinology 129(2): 145-155, 1997

The activity of transcription factor Stat5 responds to prolactin, growth hormone, and IGF-I in rat and bovine mammary explant culture. Journal of animal science 78(12): 3114-3125, 2000

Effects of Ovariectomy and Prolactin on Mammary Gland Expressions of Transforming Growth Factor alpha and Epidermal Growth Factor Receptor mRNAs in Mice. Zoological Science 15(4): 525-529, 1998

Growth hormone, acting in part through the insulin-like growth factor axis, rescues developmental, but not metabolic, activity in the mammary gland of mice expressing a single allele of the prolactin receptor. Endocrinology 143(11): 4310-4319, 2002

Treatment of ewes at different stages of pregnancy with epidermal growth factor: effects on wool growth and plasma concentrations of growth hormone, prolactin, placental lactogen and thyroxine and on foetal development. Acta Endocrinologica 105(4): 558-566, 1984

Prolactin and transforming growth factor-beta signaling exert opposing effects on mammary gland morphogenesis, involution, and the Akt-forkhead pathway. Molecular Endocrinology 18(5): 1171-1184, 2004

In vivo effect of an luteinizing hormone-releasing hormone analog on vascular endothelial growth factor and epidermal growth factor receptor expression in mammary tumors. Journal of Carcinogenesis 8: 11, 2009

Differential effects of basic fibroblast growth factor, epidermal growth factor, transforming growth factor-alpha, and insulin-like growth factor-I on a hypothalamic gonadotropin-releasing hormone neuronal cell line. Journal of Neuroscience Research 49(6): 739-749, 1997

The role of p21/CIP1/WAF1 (p21) in the negative regulation of the growth hormone/growth hormone receptor and epidermal growth factor/epidermal growth factor receptor pathways, in growth hormone transduction defect. Annals of Pediatric Endocrinology and Metabolism 23(4): 204-209, 2018

Insulin-like growth factor-I augments prolactin and inhibits growth hormone release through distinct as well as overlapping cellular signaling pathways. Comparative biochemistry and physiology Part B Biochemistry and molecular biology 129(2-3): 237-242, 2001

Effects of epidermal growth factor (EGF) and prolactin on EGF receptor cytoskeletal association in mammary epithelial cells. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 215(4): 393-398, 1997

Basic fibroblast growth factor and epidermal growth factor exert differential trophic effects on CNS neurons. Journal of Neuroscience Research 21(1): 71-79, 1988

Epidermal growth factor receptor levels increase but epidermal growth factor receptor ligand levels decrease in mouse mammary tumors during progression from hormone dependence to hormone independence. Breast Cancer Research and Treatment 26(3): 289-295, 1993

Prolactin and epidermal growth factor regulation of rat mammary epithelial cell morphogenesis growth and functional differentiation. Proceedings of the American Association for Cancer Research Annual Meeting 33: 274, 1992

Tyrosine phosphorylation of Grb2: role in prolactin/epidermal growth factor cross talk in mammary epithelial cell growth and differentiation. Molecular and Cellular Biology 29(10): 2505-2520, 2009