Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model

Rebekah A. Burich, Neelima Rakesh Mehta, Gregory T. Wurz, Jamie Lee McCall, Brittany E. Greenberg, Katie E. Bell, Stephen M Griffey, Michael W. Degregorio

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

OBJECTIVE: Ospemifene, a new drug indicated for the treatment of vulvovaginal atrophy, has completed phase III clinical trials. A condition affecting millions of women worldwide, vulvovaginal atrophy has long been treated with estrogen therapy. Estrogen treatment carries with it risks of thromboembolism, endometrial proliferative effects, and breast cancer promotion. In this study, we test the effects of three dosing levels of ospemifene in both the prevention and treatment of breast cancer in the MTag.Tg mouse model. METHODS: The polyomavirus middle-T transgenic mouse model (MTag.Tg), which produces synchronized, multifocal mammary tumors in the immunologically intact C57BL/6 background, was used to examine the impact of ospemifene treatment. First, a cell line derived from an MTag.Tg mouse tumor (MTag 34) was treated in vitro with ospemifene and its major metabolite, 4-hydroxyospemifene (4-OH ospemifene). MTag.Tg mice were treated daily by gavage with three different doses of ospemifene (5, 25, and 50 mg/kg) before or after the development of mammary tumors. Survival and tumor development results were used to determine the effect of ospemifene treatment on mammary tumors in both the preventive and treatment settings. RESULTS: Tumors and the MTag 34 cell line were positive for estrogen receptor expression. The MTag 34 line was not stimulated by ospemifene or its major, active metabolite 4-OH ospemifene in vitro. Ospemifene increased survival time and exerted an antitumor effect on the development and growth of estrogen receptor-positive mammary tumors in the MTag.Tg mouse model at the 50-mg/kg dose. The levels of ospemifene and 4-OH ospemifene in both the tumors and plasma of mice confirmed the dosing. Ospemifene did not exert an estrogenic effect in the breast tissue at doses equivalent to human dosing. CONCLUSIONS: Ospemifene prevents and treats estrogen receptor-positive MTag.Tg mammary tumors in this immune-intact mouse model in a dose-dependent fashion. Ospemifene drug levels in the plasma of treated mice were comparable with those found in humans. Combined with our previous data, ospemifene does not seem to pose a breast cancer risk in animals and slows down cancer development and progression in the MTag.Tg model.

Original languageEnglish (US)
Pages (from-to)96-103
Number of pages8
JournalMenopause
Volume19
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Breast cancer
  • Chemoprevention
  • Hormone therapy
  • Ospemifene
  • Osteoporosis
  • Vulvovaginal atrophy

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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    Burich, R. A., Mehta, N. R., Wurz, G. T., McCall, J. L., Greenberg, B. E., Bell, K. E., Griffey, S. M., & Degregorio, M. W. (2012). Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model. Menopause, 19(1), 96-103. https://doi.org/10.1097/gme.0b013e318223e82a