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

64 Citations (Scopus)

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

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Progestins
Heterografts
Vascular Endothelial Growth Factor A
Breast Neoplasms
Progesterone Congeners
Growth
Neoplasms
Therapeutics
Mifepristone
Medroxyprogesterone Acetate
Breast Diseases
Estrogen Replacement Therapy
Angiogenesis Inhibitors
Progesterone Receptors
Contraception
Nude Mice
Progesterone
Rodentia
Estrogens
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Progestin-dependent progression of human breast tumor xenografts : A novel model for evaluating antitumor therapeutics. / Liang, Yayun; Besch-Williford, Cynthia; Brekken, Rolf A.; Hyder, Salman M.

In: Cancer Research, Vol. 67, No. 20, 15.10.2007, p. 9929-9936.

Research output: Contribution to journalArticle

Liang, Yayun ; Besch-Williford, Cynthia ; Brekken, Rolf A. ; Hyder, Salman M. / Progestin-dependent progression of human breast tumor xenografts : A novel model for evaluating antitumor therapeutics. In: Cancer Research. 2007 ; Vol. 67, No. 20. pp. 9929-9936.
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