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

G.J. Allan, E. Tonner, M.C. Barber, M. Travers, J. Shand, R.G. Vernon, P.A. Kelly, N. Binart, D.J. Flint

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The heterozygous prolactin (PRL) receptor (PRLR+/−) mouse fails to develop a fully functional mammary gland at the end of the first pregnancy and shows markedly impaired lobuloalveolar development and milk secretion in young females. PRL and GH, acting through the IGF system, have interactive effects to enhance epithelial cell survival. Thus, we propose that a reduction in the expression of the PRLR may lead to increased IGFBP-5 expression (proapoptotic) and that GH may rescue mammary development by increasing IGF-I, an important mitogen and survival factor for the mammary epithelium. Mammary IGF-binding protein-5 (IGFBP-5) concentrations and plasmin activity in PRLR+/− mice were increased on d 2 postpartum, indicative of increased cell death and extracellular matrix remodeling. After GH treatment, a restoration of mammary alveolar development and a reduction in the activities of IGFBP-5 and plasmin were observed. Despite the severely impaired mammary development in PRLR+/− mice, both mRNA and protein expression for caseins and acetyl-coenzyme A (acetyl-CoA) carboxylase and acetyl-CoA caboxylase-α mRNA increased at parturition, although not to the extent in wild-type animals. Surprisingly, GH treatment actually led to a further decrease in milk protein and acetyl-CoA carboxylase-αexpression when expressed per cell. This was confirmed by the smaller alveolar size, the relative paucity of milk in the mammary glands of GH-treated animals, and the inability of their pups to gain weight. In a subsequent study IGFBP-5 was administered to wild-type mice and produced a 45% decrease in mammary DNA content, a 30% decrease in parenchymal tissue, and impaired lactation. These results suggest that GH can improve mammary development in PRLR+/− mice, but that it fails to enhance metabolic activity. This may be due to the maintenance by GH/IGF-I of a proliferative, rather than a differentiative, phenotype.
LanguageEnglish
Pages4310-4319
Number of pages10
JournalEndocrinology
Volume143
Issue number11
DOIs
Publication statusPublished - 2002

Fingerprint

Prolactin Receptors
Somatomedins
Human Mammary Glands
Growth Hormone
Insulin-Like Growth Factor Binding Protein 5
Breast
Alleles
Acetyl-CoA Carboxylase
Fibrinolysin
Insulin-Like Growth Factor I
Milk
Messenger RNA
Acetyl Coenzyme A
Wild Animals
Milk Proteins
Caseins
Mitogens
Lactation
Prolactin
Postpartum Period

Keywords

  • growth hormone
  • prolactin receptor
  • endocrinology

Cite this

Allan, G.J. ; Tonner, E. ; Barber, M.C. ; Travers, M. ; Shand, J. ; Vernon, R.G. ; Kelly, P.A. ; Binart, N. ; Flint, D.J. / 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. In: Endocrinology. 2002 ; Vol. 143, No. 11. pp. 4310-4319.
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abstract = "The heterozygous prolactin (PRL) receptor (PRLR+/−) mouse fails to develop a fully functional mammary gland at the end of the first pregnancy and shows markedly impaired lobuloalveolar development and milk secretion in young females. PRL and GH, acting through the IGF system, have interactive effects to enhance epithelial cell survival. Thus, we propose that a reduction in the expression of the PRLR may lead to increased IGFBP-5 expression (proapoptotic) and that GH may rescue mammary development by increasing IGF-I, an important mitogen and survival factor for the mammary epithelium. Mammary IGF-binding protein-5 (IGFBP-5) concentrations and plasmin activity in PRLR+/− mice were increased on d 2 postpartum, indicative of increased cell death and extracellular matrix remodeling. After GH treatment, a restoration of mammary alveolar development and a reduction in the activities of IGFBP-5 and plasmin were observed. Despite the severely impaired mammary development in PRLR+/− mice, both mRNA and protein expression for caseins and acetyl-coenzyme A (acetyl-CoA) carboxylase and acetyl-CoA caboxylase-α mRNA increased at parturition, although not to the extent in wild-type animals. Surprisingly, GH treatment actually led to a further decrease in milk protein and acetyl-CoA carboxylase-αexpression when expressed per cell. This was confirmed by the smaller alveolar size, the relative paucity of milk in the mammary glands of GH-treated animals, and the inability of their pups to gain weight. In a subsequent study IGFBP-5 was administered to wild-type mice and produced a 45{\%} decrease in mammary DNA content, a 30{\%} decrease in parenchymal tissue, and impaired lactation. These results suggest that GH can improve mammary development in PRLR+/− mice, but that it fails to enhance metabolic activity. This may be due to the maintenance by GH/IGF-I of a proliferative, rather than a differentiative, phenotype.",
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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. / Allan, G.J.; Tonner, E.; Barber, M.C.; Travers, M.; Shand, J.; Vernon, R.G.; Kelly, P.A.; Binart, N.; Flint, D.J.

In: Endocrinology, Vol. 143, No. 11, 2002, p. 4310-4319.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Allan, G.J.

AU - Tonner, E.

AU - Barber, M.C.

AU - Travers, M.

AU - Shand, J.

AU - Vernon, R.G.

AU - Kelly, P.A.

AU - Binart, N.

AU - Flint, D.J.

PY - 2002

Y1 - 2002

N2 - The heterozygous prolactin (PRL) receptor (PRLR+/−) mouse fails to develop a fully functional mammary gland at the end of the first pregnancy and shows markedly impaired lobuloalveolar development and milk secretion in young females. PRL and GH, acting through the IGF system, have interactive effects to enhance epithelial cell survival. Thus, we propose that a reduction in the expression of the PRLR may lead to increased IGFBP-5 expression (proapoptotic) and that GH may rescue mammary development by increasing IGF-I, an important mitogen and survival factor for the mammary epithelium. Mammary IGF-binding protein-5 (IGFBP-5) concentrations and plasmin activity in PRLR+/− mice were increased on d 2 postpartum, indicative of increased cell death and extracellular matrix remodeling. After GH treatment, a restoration of mammary alveolar development and a reduction in the activities of IGFBP-5 and plasmin were observed. Despite the severely impaired mammary development in PRLR+/− mice, both mRNA and protein expression for caseins and acetyl-coenzyme A (acetyl-CoA) carboxylase and acetyl-CoA caboxylase-α mRNA increased at parturition, although not to the extent in wild-type animals. Surprisingly, GH treatment actually led to a further decrease in milk protein and acetyl-CoA carboxylase-αexpression when expressed per cell. This was confirmed by the smaller alveolar size, the relative paucity of milk in the mammary glands of GH-treated animals, and the inability of their pups to gain weight. In a subsequent study IGFBP-5 was administered to wild-type mice and produced a 45% decrease in mammary DNA content, a 30% decrease in parenchymal tissue, and impaired lactation. These results suggest that GH can improve mammary development in PRLR+/− mice, but that it fails to enhance metabolic activity. This may be due to the maintenance by GH/IGF-I of a proliferative, rather than a differentiative, phenotype.

AB - The heterozygous prolactin (PRL) receptor (PRLR+/−) mouse fails to develop a fully functional mammary gland at the end of the first pregnancy and shows markedly impaired lobuloalveolar development and milk secretion in young females. PRL and GH, acting through the IGF system, have interactive effects to enhance epithelial cell survival. Thus, we propose that a reduction in the expression of the PRLR may lead to increased IGFBP-5 expression (proapoptotic) and that GH may rescue mammary development by increasing IGF-I, an important mitogen and survival factor for the mammary epithelium. Mammary IGF-binding protein-5 (IGFBP-5) concentrations and plasmin activity in PRLR+/− mice were increased on d 2 postpartum, indicative of increased cell death and extracellular matrix remodeling. After GH treatment, a restoration of mammary alveolar development and a reduction in the activities of IGFBP-5 and plasmin were observed. Despite the severely impaired mammary development in PRLR+/− mice, both mRNA and protein expression for caseins and acetyl-coenzyme A (acetyl-CoA) carboxylase and acetyl-CoA caboxylase-α mRNA increased at parturition, although not to the extent in wild-type animals. Surprisingly, GH treatment actually led to a further decrease in milk protein and acetyl-CoA carboxylase-αexpression when expressed per cell. This was confirmed by the smaller alveolar size, the relative paucity of milk in the mammary glands of GH-treated animals, and the inability of their pups to gain weight. In a subsequent study IGFBP-5 was administered to wild-type mice and produced a 45% decrease in mammary DNA content, a 30% decrease in parenchymal tissue, and impaired lactation. These results suggest that GH can improve mammary development in PRLR+/− mice, but that it fails to enhance metabolic activity. This may be due to the maintenance by GH/IGF-I of a proliferative, rather than a differentiative, phenotype.

KW - growth hormone

KW - prolactin receptor

KW - endocrinology

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DO - 10.1210/en.2001-211191

M3 - Article

VL - 143

SP - 4310

EP - 4319

JO - Endocrinology

T2 - Endocrinology

JF - Endocrinology

SN - 0013-7227

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ER -