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

Abstract

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 ovariectomized wild-type (WT) and ERβ knockout (ERβKO) 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 ERβKO animals receiving either treatment. For the first time, we showed that E 2 alters the growth of nontransformed colonocytes in vitro and that, through an ERβ-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]

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

“…As early as a few hours following carcinogen exposure at the point of initial DNA damage, E 2 significantly induces apoptosis in the colonic epithelium of rats when compared with control mice (Armstrong et al 2011). In addition, we have demonstrated that E 2 suppresses the formation of premalignant lesions in the colon, which is again associated with an upregulation of apoptosis in colonic epithelia (Weige et al 2009). …”

“…Previous studies carried out in our laboratory and others have indicated that ERb, the primary ER within the colon, is the form of the receptor through which E 2 exerts its protective effects (Guo et al 2004, Weige et al 2009. Other groups have shown that ERbKO mice are more susceptible to inflammation-associated colon cancer than the WT mice (Saleiro et al 2012).…”

Colorectal Cancer Risk Associated with Hormone Use Varies by Expression of Estrogen Receptor-β

“…In experimental cell line and animal studies, protective effects of female sex hormones about colorectal carcinogenesis were found to be mediated by ESR2 (24)(25)(26)(27)(28)(29). Therefore, it is biologically plausible that exogenous hormones interact with ESR2 and downregulate the growth of neoplastic cells in the colorectal mucosa.…”

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

“…The YAMC cell line was initially generated from the Immorto mouse (Whitehead et al, 1993) and has been previously used in our studies (Kolar et al, 2007;Weige et al, 2009;Turk et al, 2011). Cells were maintained in RPMI 1640 medium with 5% fetal bovine serum, 5 units/ml mouse interferon-g (IF005) (EMD Millipore, Billerica, MA), 1% ITS "2" minus (insulin, transferrin, selenium) (41-400-045; Life Technologies, Grand Island, NY) at 33°C (permissive conditions).…”