Progestin-dependent progression of human breast tumor xenografts: A novel model for evaluating antitumor therapeutics

Yayun Liang, Cynthia Besch-Williford, Rolf A. Brekken, Salman M. Hyder

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Recent clinical trials indicate that synthetic progestins may stimulate progression of breast cancer in postmenopausal women, a result that is consistent with studies in chemically-induced breast cancer models in rodents. However, progestin-dependent progression of breast cancer tumor xenografts has not been shown. This study shows that xenografts obtained from BT-474 and T47-Dhuman breast cancer cells without Matrigel in estrogen-supplemented nude mice begin to regress within days after tumor cell inoculation. However, their growth is resumed if animals are supplemented with progesterone. The antiprogestin RU-486 blocks progestin stimulation of growth, indicating involvement of progesterone receptors. Exposure of xenografts to medroxyprogesterone acetate, a synthetic progestin used in postmenopausal hormone replacement therapy and oral contraception, also stimulates growth of regressing xenograft tumors. Tumor progression is dependent on expression of vascular endothelial growth factor (VEGF); growth of progestin-dependent tumors is blocked by inhibiting synthesis of VEGF or VEGF activity using a monoclonal anti-VEGF antibody (2C3) or by treatment with PRIMA-1, a small-molecule compound that reactivates mutant p53 into a functional protein and blocks VEGF production. These results suggest a possible model system for screening potential therapeutic agents for their ability to prevent or inhibit progestin-dependent human breast tumors. Such a model could potentially be used to screen for safer antiprogestins, antiangiogenic agents, or for compounds that reactivate mutant p53 and prevent progestin-dependent progression of breast disease.

Original languageEnglish (US)
Pages (from-to)9929-9936
Number of pages8
JournalCancer research
Volume67
Issue number20
DOIs
StatePublished - Oct 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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