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Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice

Liang, Yayun PhD1; Benakanakere, Indira PhD1,2; Besch-Williford, Cynthia DVM, PhD3; Hyder, Ryyan S. BS1; Ellersieck, Mark R. PhD4; Hyder, Salman M. PhD1,2

doi: 10.1097/gme.0b013e3181d3dd0c
Articles

Objective: Previous studies have shown that sequential exposure to estrogen and progesterone or medroxyprogesterone acetate (MPA) stimulates vascularization and promotes the progression of BT-474 and T47-D human breast cancer cell xenografts in nude mice (Liang et al, Cancer Res 2007, 67:9929). In this follow-up study, the effects of progesterone, MPA, norgestrel (N-EL), and norethindrone (N-ONE) on BT-474 xenograft tumors were compared in the context of several different hormonal environments. N-EL and N-ONE were included in the study because synthetic progestins vary considerably in their biological effects and the effects of these two progestins on the growth of human tumor xenografts are not known.

Methods: Estradiol-supplemented intact and ovariectomized immunodeficient mice were implanted with BT-474 cells. Progestin pellets were implanted simultaneously with estradiol pellets either 2 days before tumor cell injection (ie, combined) or 5 days after tumor cell injections (ie, sequentially).

Results: Progestins stimulated the growth of BT-474 xenograft tumors independent of exposure timing and protocol, MPA stimulated the growth of BT-474 xenograft tumors in ovariectomized mice, and progestins stimulated vascular endothelial growth factor elaboration and increased tumor vascularity. Progestins also increased lymph node metastasis of BT-474 cells. Therefore, progestins, including N-EL and N-ONE, induce the progression of breast cancer xenografts in nude mice and promote tumor metastasis.

Conclusions: These observations suggest that women who ingest progestins for hormone therapy or oral contraception could be more at risk for developing breast cancer because of proliferation of existing latent tumor cells. Such risks should be considered in the clinical setting.

The observations in this article suggest that women who ingest progestins for hormone therapy or oral contraception could be more at risk for developing breast cancer because of proliferation of existing latent tumor cells.

From the 1Department of Biomedical Sciences, 2Dalton Cardiovascular Research Center, 3Department of Pathobiology, and 4Agriculture Experiment Station, University of Missouri, Columbia, MO.

Received December 1, 2009; revised and accepted January 7, 2010.

Funding/support: This work was supported by National Institutes of Health grant CA-86916, Komen for Cure grant BCTR 0600704, a COR award from the College of Veterinary Medicine, and research funds from RADIL, University of Missouri.

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Salman M. Hyder, PhD, Dalton Cardiovascular Research Center, 134 Research Park Drive, Columbia, MO 65211. E-mail: hyders@missouri.edu

©2010The North American Menopause Society