Progesterone receptor inhibits aromatase and inflammatory response pathways in breast cancer cells via ligand-dependent and ligand-independent mechanisms

Mol Endocrinol. 2008 Aug;22(8):1812-24. doi: 10.1210/me.2007-0443. Epub 2008 May 15.

Abstract

Aromatase (product of CYP19 gene), the critical enzyme in estrogen biosynthesis, is up-regulated in 70% of all breast cancers and is highly correlated with cyclooxygenase 2 (COX-2), the rate-determining enzyme in prostanoid biosynthesis. Expression of COX-2 also is correlated with the oncogene HER-2/neu. The efficacy of current endocrine therapies for breast cancer is predicted only if the tumor contains significant amounts of estrogen receptor. Because the progesterone receptor (PR) is an estrogen-induced target gene, it has been suggested that its presence may serve as an indicator of estrogen receptor functional capacity and the differentiation state of the tumor. In the present study, we tested the hypothesis that PR serves a crucial protective role by antagonizing inflammatory response pathways in the breast. We observed that progesterone antagonized the stimulatory effects of cAMP and IL-1beta on aromatase, COX-2, and HER-2/neu expression in T47D breast cancer cells. These actions of progesterone were associated with increased expression of the nuclear factor-kappaB inhibitor, IkappaBalpha. In 28 breast cancer cell lines, IkappaBalpha expression was positively correlated with PR mRNA levels; overexpression of a phosphorylation-defective mutant of IkappaBalpha inhibited expression of aromatase, COX-2, and HER-2/neu. Moreover, in breast cancer cell lines cultured in the absence of progesterone, up-regulation of endogenous PR caused decreased expression of aromatase, COX-2, and HER-2/neu expression, whereas down-regulation of endogenous PR resulted in a marked induction of aromatase and HER-2/neu mRNA. Collectively, these findings suggest that PR plays an important antiinflammatory role in breast cancer cells via ligand-dependent and ligand-independent mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aromatase / biosynthesis
  • Aromatase / metabolism*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cyclic AMP / pharmacology
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics
  • Enzyme Induction / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • I-kappa B Proteins / metabolism
  • Inflammation / enzymology*
  • Interleukin-1beta / pharmacology
  • Ligands
  • NF-KappaB Inhibitor alpha
  • Progesterone / pharmacology
  • Protein Binding / drug effects
  • Protein Isoforms / metabolism
  • RNA, Small Interfering / metabolism
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptors, Progesterone / metabolism*
  • Response Elements
  • Transcription Factor RelA / metabolism

Substances

  • I-kappa B Proteins
  • Interleukin-1beta
  • Ligands
  • NFKBIA protein, human
  • Protein Isoforms
  • RNA, Small Interfering
  • Receptors, Progesterone
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Progesterone
  • Cyclic AMP
  • Aromatase
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Receptor, ErbB-2