IGF-2 Is a Mediator of Prolactin-Induced Morphogenesis in the Breast

Dev Cell. 2002 Dec;3(6):877-87. doi: 10.1016/s1534-5807(02)00365-9.

Abstract

The mechanisms by which prolactin controls proliferation of mammary epithelial cells (MECs) and morphogenesis of the breast epithelium are poorly understood. We show that cyclin D1(-/-) MECs fail to proliferate in response to prolactin and identify IGF-2 as a downstream target of prolactin signaling that lies upstream of cyclin D1 transcription. Ectopic IGF-2 expression restores alveologenesis in prolactin receptor(-/-) epithelium. Alveologenesis is retarded in IGF-2-deficient MECs. IGF-2 and prolactin receptor mRNAs colocalize in the mammary epithelium. Prolactin induces IGF-2 mRNA and IGF-2 induces cyclin D1 protein in primary MECs. Thus, IGF-2 is a mediator of prolactin-induced alveologenesis; prolactin, IGF-2, and cyclin D1, all of which are overexpressed in breast cancers, are components of a developmental pathway in the mammary gland.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Carcinoma / genetics
  • Carrier Proteins
  • Cell Division / genetics*
  • Cells, Cultured
  • Cyclin D1 / deficiency*
  • Cyclin D1 / genetics
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Female
  • Gene Expression Regulation, Developmental / genetics*
  • Genes / drug effects
  • Genes / genetics
  • Genetic Testing
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism*
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / embryology*
  • Mammary Glands, Animal / metabolism
  • Membrane Glycoproteins
  • Mice
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Progesterone / metabolism
  • Progesterone / pharmacology
  • Prolactin / genetics
  • Prolactin / metabolism*
  • Prolactin / pharmacology
  • RANK Ligand
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Progesterone / deficiency
  • Receptors, Progesterone / genetics
  • Signal Transduction / genetics

Substances

  • Carrier Proteins
  • Membrane Glycoproteins
  • RANK Ligand
  • RNA, Messenger
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Progesterone
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Cyclin D1
  • Progesterone
  • Insulin-Like Growth Factor II
  • Prolactin