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

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-D human 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.

• Authors: Yayun Liang, Cynthia Besch-Williford, Rolf A Brekken, Salman M Hyder
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 20 Pg. 9929-36 (Oct 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17942925 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Progesterone Congeners
• Progestins
• Receptors, Estrogen
• Receptors, Progesterone
• Vascular Endothelial Growth Factor A
• Mifepristone
• Progesterone
• Medroxyprogesterone Acetate
• Vascular Endothelial Growth Factor Receptor-2
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Aza Compounds (pharmacology)
• Breast Neoplasms (blood supply, drug therapy, pathology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Growth Processes (drug effects)
• Disease Progression
• Female
• Humans
• Medroxyprogesterone Acetate (pharmacology)
• Mice
• Mifepristone (pharmacology)
• Neoplasms, Hormone-Dependent (blood supply, drug therapy, pathology)
• Neovascularization, Pathologic (drug therapy, pathology)
• Progesterone (pharmacology)
• Progesterone Congeners (pharmacology)
• Progestins (antagonists & inhibitors, pharmacology)
• Receptors, Estrogen (biosynthesis)
• Receptors, Progesterone (biosynthesis)
• Vascular Endothelial Growth Factor A (biosynthesis)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Xenograft Model Antitumor Assays