Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis

Cancer Res. 2010 Nov 1;70(21):8927-36. doi: 10.1158/0008-5472.CAN-10-1238. Epub 2010 Oct 19.

Abstract

Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed preexisting disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER(-) 2008 and ER(+) PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER(+) tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ERs are functional and foster aggressiveness. Laser-captured human EOC cells from ER(-) and ER(+) xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E2-regulated EOC genes were defined, but <10% were shared with E2-regulated breast cancer genes. Because breast cancer selective ER modulators (SERM) are therapeutically ineffective in EOC, we suggest that our EOC-specific E2-regulated genes can assist pharmacologic discovery of ovarian-targeted SERM.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Estrogens / pharmacology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immunoenzyme Techniques
  • Lymphatic Metastasis
  • Mice
  • Mice, Nude
  • Oligonucleotide Array Sequence Analysis
  • Organ Specificity
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / secondary*
  • RNA, Messenger / genetics
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Selective Estrogen Receptor Modulators / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Estrogens
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Selective Estrogen Receptor Modulators