Estrogen receptor functional activity changes during differentiation of mammary epithelial cells

Mol Endocrinol. 2004 Feb;18(2):412-21. doi: 10.1210/me.2003-0290. Epub 2003 Nov 6.


Mammary gland development involves complex cycles of proliferation, differentiation, and morphogenesis, regulated by hormones including estrogens, prolactin (PRL), and epidermal growth factor (EGF). The mouse mammary epithelial cell line HC11 has been shown to be valuable for investigations of differentiation of mammary gland. In this study, we show that HC11 cells express estrogen receptor (ER)alpha and ER beta proteins at all developmental stages. We have established two different stable HC11 cell lines; H-estrogen response element (ERE) containing an ERE-reporter and H-Bc containing a beta-casein reporter. Transcription of the ERE-reporter was activated only in proliferating cells in the presence of EGF. When the cells entered the differentiation program, in the absence of EGF, estradiol-induced transcription of the ERE reporter was repressed, and similar results were obtained when MAPK signaling was inhibited in proliferating cells. We propose that these findings are related to changes in ER corepressor levels, regulated by EGF. We also report that the beta-casein reporter was activated in terminally differentiated cells and that this induction was effectively repressed by estradiol treatment. Finally, we show a physical interaction between endogenous ER alpha and signal transducer and activator of transcription 5 in differentiated HC11 cells. In summary, our results show that ER functional activity changes during differentiation of HC11 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caseins / genetics
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Female
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • MAP Kinase Signaling System / drug effects
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / metabolism
  • Mice
  • Milk Proteins / genetics
  • Milk Proteins / metabolism
  • Promoter Regions, Genetic
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Response Elements
  • STAT5 Transcription Factor
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription, Genetic


  • Caseins
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Milk Proteins
  • Nr0b1 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • STAT5 Transcription Factor
  • Trans-Activators
  • nuclear receptor subfamily 0, group B, member 2
  • Estradiol
  • Epidermal Growth Factor