Progesterone-independent effects of human progesterone receptors (PRs) in estrogen receptor-positive breast cancer: PR isoform-specific gene regulation and tumor biology

Mol Endocrinol. 2005 Mar;19(3):574-87. doi: 10.1210/me.2004-0287. Epub 2004 Nov 24.


Progesterone receptors (PRs) are prognostic markers in breast cancers irrespective of the patient's progestational status. However, there are two PR isoforms, PR-A and PR-B, that are equimolar in the normal breast but dysregulated in advanced disease. Postmenopausal, tamoxifen-treated patients with estrogen receptor (ER)-positive, PR-A-rich tumors have much faster disease recurrence than patients with PR-B-rich tumors. To study the mechanisms we engineered ER+ breast cancer cells that express each PR isoform under control of an inducible promoter. We identified 79 genes regulated by progesterone (P), mainly by PR-B, and 51 genes regulated without progesterone, mainly by PR-A. Only nine genes were regulated with and without ligand, leading to definition of three classes: I) genes regulated only by liganded PR; II) genes regulated only by unliganded PR; III) genes regulated by both. Unliganded PR-A and PR-B differentially regulate genes that coordinate extracellular signaling pathways and influence tumor cell biology. Indeed, in the absence of P, compared with ER+/PR-B+ or PR- cells, ER+, PR-A+ cells exhibit an aggressive phenotype, are more adhesive to an extracellular matrix, and are more migratory. Additionally, unliganded PR-A and PR-B both inhibit cell growth and provoke resistance to Taxol-induced apoptosis. We propose that PR-A:PR-B ratios, even in the absence of P, influence the biology and treatment response of ER+ tumors, that PR-A isoforms are functionally dominant in P-deficient states, and that PR-A rich tumors are especially aggressive.

Publication types

  • Research Support, N.I.H., Extramural
  • 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

  • Apoptosis
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Ligands
  • Microscopy, Confocal
  • Neoplasm Metastasis
  • Neoplasms / metabolism
  • Paclitaxel / pharmacology
  • Progesterone / metabolism*
  • Promoter Regions, Genetic
  • Protein Isoforms
  • RNA, Messenger / metabolism
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / chemistry
  • Receptors, Progesterone / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic


  • Ligands
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, Progesterone
  • progesterone receptor A
  • progesterone receptor B
  • Progesterone
  • Paclitaxel