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Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats

Authors' Affiliations: ¹ Dalton Cardiovascular Research Center and Department of Biomedical Sciences, ² Department of Veterinary Pathology, and ³ Department of Statistics, University of Missouri, Columbia, Missouri and ⁴ Oral and Pharyngeal Cancer Branch, NIH, Bethesda, Maryland

Requests for reprints: Salman M. Hyder, Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri, 134 Research Park Drive, Columbia, MO 65211. Phone: 573-882-1261; Fax: 573-884-4232; E-mail: hyders{at}missouri.edu.

Purpose: Synthetic progestins are widely used therapeutically; however, there is controversy regarding their proliferative effects. We used a rat 7,12-dimethylbenz[a]anthracene (DMBA)–induced mammary tumor model to test the hypothesis that progestins increase angiogenesis and as a result decrease the latency period and increase the multiplicity of mammary tumors.

Experimental Design: Medroxyprogesterone acetate (MPA) pellets were implanted 2, 4, or 6 weeks after DMBA exposure; RU-486 was given 3 days before MPA. Experiments were concluded 70 days after DMBA administration.

Results: MPA exposure 4 or 6 weeks after DMBA reduced the latency period for appearance of tumors in a dose-dependent manner and increased tumor incidence. Administration of MPA 2 weeks after DMBA administration reduced tumor incidence and was protective. Progesterone did not reduce the latency period but significantly increased tumor incidence. RU-486 delayed the latency period and decreased tumor incidence in animals exposed to MPA at 4 weeks after DMBA treatment, indicating that the progesterone receptor may be partially responsible for transmission of proliferative signals. RU-486 also delayed the latency period but failed to reduce overall tumor incidence when animals were exposed to MPA at 6 weeks after DMBA treatment, indicating that other factors may also control MPA-induced acceleration. Whereas MPA-accelerated tumors were both intraductal and tubular, progesterone-accelerated and/or DMBA-induced tumors were tubular. Progestin treatment increased vascular endothelial growth factor expression within tumors in a ligand- and cell type–dependent manner and increased angiogenesis in correlation with vascular endothelial growth factor expression. No mammary tumors or progesterone receptor were detected in DMBA-treated ovariectomized rats regardless of progestin administration.

Conclusions: We propose that progestins can accelerate the development of mammary tumors and that antiangiogenic agents and/or the use of antiprogestins that can reduce tumor incidence might be a viable therapeutic option for treatment of progestin-accelerated tumors. The model described here is a potentially useful preclinical model for rapidly screening such compounds.

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