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.
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.
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).
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.
Supplemental digital content is available in the text.
From the Wake Forest University Primate Center and the Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
Received January 5, 2012; revised and accepted February 27, 2012.
Funding/support: This work was supported by grants from Pfizer, Inc. (aninvestigator-initiated grant to Wake Forest School of Medicine; principal investigator, T.B.C.), the National Center of Research Resources (NCRR; 5T32 RR07009-32 to K.F.E. and K01 RR 021322-05 to C.E.W.), and intramural support from the Department of Pathology, Wake Forest School of Medicine (C.E.W.).
Financial disclosure/conflicts of interests: Wake Forest School of Medicine has received an investigator-initiated (T.B.C.) grant (bazedoxifene acetate) from Pfizer. T.B.C., C.E.W., and S.E.A. were paid coinvestigators and K.F.E. was a paid research fellow on this grant. J.M.C. and T.C.R. were unpaid coinvestigators. T.B.C. and J.M.C. have been paid consultants for Pfizer, and J.M.C. is the principal investigator on a pending investigator-initiated proposal to Pfizer related to bazedoxifene acetate.
The contents are solely the responsibility of the authors and do not necessarily represent the view of the National Institutes of Health, NCRR, or Pfizer.
Portions of this work were presented at the 93rd Annual Meeting of the Endocrine Society, June 4-7, 2011, Boston, MA (abstract P1-16).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.menopause.org).
Address correspondence to: Kelly F. Ethun, DVM, Wake Forest University Primate Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem 27157-1040, NC. E-mail: Kelly.Ethun@gmail.com