Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

Numerous clinical and animal studies show that hormone replacement therapy reduces the risk of colon tumor formation. However, the majority of experiments have shown that estradiol (E-2) does not inhibit the growth of malignantly transformed colon epithelia. As such, the presented studies focused on evaluating the effects of E-2 in noncancerous colonocytes. E-2 treatments (0-10 nmol/L) reduced cell growth and increased apoptotic activity in young adult mouse colonocytes (YAMC), a nonmalignant cell line, in a dose-responsive manner. These effects were lost in the YAMC-Ras cells, an isogenic cell line with a single malignant transformation. Cotreatment with an estrogen receptor (ER) antagonist inhibited the physiologic effects of E-2 in YAMC cells, suggesting that the response is ER mediated. To further study the effect of E-2 on colonic epithelia, we evaluated the development of preneoplastic lesions in ovariectornized wild-type (WT) and ER beta knockout (ER beta KO) mice treated with either vehicle or E-2. WT E-2-treated animals exhibited significantly fewer aberrant crypt foci and increased apoptotic activity in colonic epithelia when compared with WT control mice or ER beta KO animals receiving either treatment. For the first time, we showed that E-2 alters the growth of nontransfornied colonocytes in vitro and that, through an ER beta-mediated mechanism, E-2 influences the physiology of noncancerous colonocytes, resulting in fewer preneoplastic lesions. Collectively, these data show that the protective actions of E-2 occur primarily during the initiation/promotion stages of disease development and identify the hormone as an important chemoprotective agent. [Cancer Res 2009;69(23):9118-24]