Short-term exposure to estrogen and progesterone induces partial protection against N-nitroso-N-methylurea-induced mammary tumorigenesis in Wistar±Furth rats Daniel Medina a, * , Leif E. Peterson b , Ricardo Moraes a , Jason Gay a a Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA b Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Received 15 September 2000; received in revised form 27 February 2001; accepted 20 March 2001 Abstract The lifetime protective effect of a full term pregnancy for breast cancer is a reproducible and consistent ®nding in human beings and in rodent models. The duration of pregnancy necessary to confer protection has yielded contradictory results. As the administration of estrogen and progesterone mimics the full-term pregnancy effect on conferring protection, we examined whether short-term exposure to estrogen and progesterone confers protection against N-nitroso-N-methylurea-induced mammary carcinogenesis in Wistar±Furth rats. The results reported herein show that treatment of rats with estrogen or progesterone alone for 21 days does not confer protection, but a 10-day exposure to the same concentrations of estrogen and progesterone induced a partial protective effect. The signi®cance of these results are discussed in terms of the contradictory results in the literature and the role of morphological differentiation in conferring the protective effect. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Estrogen; Progesterone; Protection; Mammary carcinogenesis 1. Introduction Reproductive history is a consistent risk factor for human breast cancer [1,2]. Early menarche, late menopause, parity, age of ®rst pregnancy, and extent of lactation are each independent risk factors [1,3]. Whereas early menarche and total years of hormone exposure are risk factors for increased incidence, early age of ®rst pregnancy #20 years of age) is a strong protective factor (one-half the risk) compared against nulliparous women [4]. The protective effect of early ®rst pregnancy has been repeatedly demonstrated in numerous epidemiological studies and provides a physiologically-operative model to achieve a practical and affordable prevention of breast cancer in humans [3,5]. In rodents, as in humans, a full-term pregnancy markedly inhibits subsequent chemical carcinogen- induced mammary tumorigenesis. This result has been demonstrated by numerous investigators over the span of the last 30 years in both rats [6±15] and mice [16]. The protective effect of pregnancy was observed even when the carcinogen was administered 100±130 days after the ®rst parturition indicating a long-lasting alteration in the state of sensitivity of the mammary gland [6]. The protective effects of pregnancy can be mimicked by administration of estrogen and progesterone [14,15]. The experiments Cancer Letters 169 (2001) 1±6 0304-3835/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3835(01)00507-9 www.elsevier.com/locate/canlet * Corresponding author.