title: Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys.
abstract: OBJECTIVE
  Concerns about increased breast cancer risk with estrogen and progestin therapy have led to an increased interest in progestin alternatives. The main objective of this study was to determine if bazedoxifene acetate (BZA), a new selective estrogen receptor modulator, will antagonize the proliferative and transcriptional effects of conjugated equine estrogens (CEE) in the breast.
  
  
  METHODS
  As part of a 20-month preclinical trial, 95 ovariectomized cynomolgus macaques (Macaca fascicularis) were randomized to receive no treatment or treatment with BZA (20 mg/d), CEE (0.45 mg/d), or BZA and CEE in combination (women's daily equivalent doses). The data presented here include breast effects after 6 months of treatment. Endpoints included histomorphometry, histopathological evaluations, gene microarray assays, polymerase chain reaction quantification of specific estrogen receptor α (ER-α) activity markers, and immunohistochemical detection of sex steroid receptors, and the proliferation marker Ki67.
  
  
  RESULTS
  BZA + CEE and BZA resulted in significantly less total epithelial density, lobular enlargement, and Ki67 immunolabeling in the terminal ducts compared with CEE alone (P < 0.05 for all). The addition of BZA to CEE antagonized the expression of ER-α-regulated genes such as GREB1 and TFF1 (P < 0.01 for both), whereas BZA alone had minimal effects on ER-α-mediated transcriptional activity. BZA and BZA + CEE did not significantly up-regulate genes related to cell cycle progression and proliferation. BZA with and without CEE also resulted in less lobular and terminal duct ER-α immunolabeling compared with control and CEE (P < 0.0001 for all).
  
  
  CONCLUSIONS
  These findings demonstrate that BZA given at a clinically relevant dose is an estrogen antagonist in the breast, supporting the idea that CEE + BZA may provide a lower breast cancer risk profile compared with traditional estrogen + progestin therapies.
authors.affiliation: Wake Forest University Primate Center and the Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157-1040, USA. Kelly.Ethun@gmail.com
authors.forename: Kelly F
authors.initials: KF
authors.lastname: Ethun
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
authors.forename: Susan E
authors.initials: SE
authors.lastname: Appt
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Clarkson
mesh_terms: D000818:Animals; D001706:Biopsy / Q000662:veterinary; D001943:Breast Neoplasms / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000166:cytology; D047628:Estrogen Receptor alpha / Q000187:drug effects; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects*; D005260:Female; D007211:Indoles / Q000008:administration & dosage*; D019394:Ki-67 Antigen / Q000032:analysis; D008252:Macaca fascicularis; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D023421:Models, Animal; D010052:Ovariectomy; D012307:Risk Factors; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*
chemical_list: D047628:Estrogen Receptor alpha; D004966:Estrogens, Conjugated (USP); D007211:Indoles; D019394:Ki-67 Antigen; D020845:Selective Estrogen Receptor Modulators; C447119:bazedoxifene