title: Progesterone receptor antagonism inhibits progestogen-related carcinogenesis and suppresses tumor cell proliferation.
abstract: Blockade of the progestogen-progesterone receptor (PR) axis is a novel but untested strategy for breast cancer prevention. We report preclinical data evaluating telapristone acetate (TPA), ulipristal acetate (UPA), and mifepristone.
  
  
  
  Tumors were induced with medroxyprogesterone acetate (MPA) plus 7,12-dimethylbenz[a]anthracene (DMBA) in mice, and MPA or progesterone plus N-methyl-N-nitrosourea (MNU) in rats. Mammary gland histology, tumor incidence, latency, multiplicity, burden and histology were evaluated, along with immunohistochemical labeling of pHH3 (proliferation), CD34 (angiogenesis), and estrogen and progesterone receptors (ER and PR). A concentration gradient of TPA, UPA, and mifepristone was tested for growth inhibition of T47D spheroids.
  
  
  
  In mouse mammary glands, no tumors formed, but TPA opposed the pro-hyperplastic effects of MPA (p = 0.002). In rats, TPA decreased tumor incidence (p = 0.037 for MPA + TPA vs. MPA, and p = 0.032 for progesterone + TPA vs. progesterone) and tumor burden (p = 0.042 for progesterone + TPA vs. progesterone), with significant decreases in pHH3 and CD34 positive cells. TPA and UPA were superior to mifepristone in growth inhibition of T47D spheroids.
  
  
  
  TPA has consistent anti-tumorigenic effects in several models, which are accompanied by decreases in cell proliferation, angiogenesis, and hormone receptor expression.
authors.affiliation: Department of Surgery, Northwestern University, Chicago, IL, USA.
authors.forename: Oukseub
authors.initials: O
authors.lastname: Lee
authors.affiliation: Department of Surgery, Northwestern University, Chicago, IL, USA.
authors.forename: Mi-Ran
authors.initials: MR
authors.lastname: Choi
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Christov
authors.affiliation: Department of Surgery, Northwestern University, Chicago, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ivancic
authors.affiliation: Department of Surgery, Northwestern University, Chicago, IL, USA; Feinberg College of Medicine, The Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL, USA. Electronic address: skhan@nm.org.
authors.forename: Seema A
authors.initials: SA
authors.lastname: Khan
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017258:Medroxyprogesterone Acetate; D008770:Methylnitrosourea; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology*; D009389:Neovascularization, Pathologic; D009649:Norpregnadienes / Q000494:pharmacology*; D011374:Progesterone; D011372:Progestins; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D018952:Antigens, CD34; D018931:Antineoplastic Agents, Hormonal; D006727:Hormone Antagonists; D009649:Norpregnadienes; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C461063:telapristone acetate; D015735:Mifepristone; D011374:Progesterone; D015127:9,10-Dimethyl-1,2-benzanthracene; D008770:Methylnitrosourea; C094854:ulipristal; D017258:Medroxyprogesterone Acetate
keywords: Mammary carcinogenesis; Prevention; Progesterone receptor; Progestogen; Rats; Telapristone acetate