New human breast cancer cells to study progesterone receptor isoform ratio effects and ligand-independent gene regulation

J Biol Chem. 2002 Aug 2;277(31):27793-800. doi: 10.1074/jbc.M202584200. Epub 2002 May 20.


All known progesterone target cells coexpress two functionally different progesterone receptor (PR) isoforms: 120-kDa B-receptors (PR-B) and N-terminally truncated, 94-kDa A-receptors (PR-A). Their ratio varies in normal and malignant tissues. In human breast cancer cells, homodimers of progesterone-occupied PR-A or PR-B regulate different gene subsets. To study PR homo- and heterodimers, we constructed breast cancer cell lines in which isoform expression is controlled by an inducible system. PR-negative cells or cells that stably express one or the other isoform were used to construct five sets of cells: (i) PR-negative control cells (Y iNull), (ii) inducible PR-A cells (Y iA), (iii) inducible PR-B cells (Y iB), (iv) stable PR-B plus inducible PR-A cells (B iA), and (v) stable PR-A plus inducible PR-B cells (A iB). Expression levels of each isoform and/or the PR-A/PR-B ratios could be tightly controlled by the dose of inducer as demonstrated by immunoblotting and transcription studies. Induced PRs underwent normal progestin-dependent phosphorylation and down-regulation and regulated exogenous promoters as well as endogenous gene expression. Transcription of exogenous promoters was dependent on the PR-A/PR-B ratio, whereas transcription of endogenous genes was more complex. Finally, we have described several genes that are regulated by induced PR-A even in the absence of ligand.

Publication types

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

MeSH terms

  • Breast Neoplasms / genetics*
  • Dimerization
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Ligands
  • Plasmids
  • Progesterone Congeners / pharmacology
  • Promegestone / pharmacology
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / genetics*
  • Transcription, Genetic
  • Tumor Cells, Cultured


  • Ligands
  • Progesterone Congeners
  • Receptors, Progesterone
  • progesterone receptor A
  • progesterone receptor B
  • Promegestone