title: Natural and synthetic progestins accelerate 7,12-dimethylbenz[a]anthracene-initiated mammary tumors and increase angiogenesis in Sprague-Dawley rats.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Indira
authors.initials: I
authors.lastname: Benakanakere
authors.forename: Cynthia
authors.initials: C
authors.lastname: Besch-Williford
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schnell
authors.forename: Sandra
authors.initials: S
authors.lastname: Brandt
authors.forename: Mark R
authors.initials: MR
authors.lastname: Ellersieck
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Salman M
authors.initials: SM
authors.lastname: Hyder
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D015735:Mifepristone / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000473:pathology; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000187:drug effects; D013997:Time Factors; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis
chemical_list: D002273:Carcinogens; D004343:Drug Implants; D011980:Receptors, Progesterone; D042442:Vascular Endothelial Growth Factors; D015735:Mifepristone; D011374:Progesterone; D015127:9,10-Dimethyl-1,2-benzanthracene; D017258:Medroxyprogesterone Acetate