MOLECULAR MECHANISMS OF ESTROGEN RECEPTOR BETA ACTION IN COLORECTAL CARCINOGENESIS

Colorectal cancer (CRC) is a major public health problem in the world population, which emphasizes the need to study novel molecular targets in order to develop alternative chemopreventive and chemotherapeutic strategies against it. Estrogens have been shown to exert a protective role against CRC and its actions seem to be mediated by estrogen receptor β (ERβ). However, further studies are required to elucidate the role of ERβ in the colon. To achieve this goal, we evaluated the effects of ERβ deficiency in sporadic CRC and colitis-associated CRC (CAC) by using two in vivo models. In addition, we stably transfected RKO colon cancer cells to overexpress ERβ and identify novel molecules regulated by ERβ signaling in vitro. In the sporadic CRC in vivo model, azoxymethane (AOM)-treated ERβ knockout (βERKO) mice showed a significantly higher incidence and multiplicity of colonic preneoplastic lesions compared to AOM-treated ERα knockout and wild-type (WT) mice. These results were associated with a loss of normal colonic crypt organization and a decrease in apoptosis rates suggesting that ERβ is the ER subtype with a protective role against sporadic CRC progression. Confirming this hypothesis, we observed that AOM-treated βERKO mice presented a significantly higher incidence of adenomas than WT mice. By real time-polymerase chain reaction and immunohistochemistry analyses, ERβ-deficient adenomas were shown to be more proliferative and less differentiated than adenomas in WT mice. Furthermore, in the CAC in vivo model, βERKO mice developed more severe clinical colitis compared to WT mice, as evidenced by significantly higher disease activity index, weight to length ratio of the colons, inflammation score, and grade of dysplasia. ERβ-deficient tumors were characterized by a significant increase in pro-inflammatory xv molecules, suggesting that ERβ might exert anti-inflammatory effects in CAC. Moreover, in vitro results revealed a novel molecular mechanism by which ERβ might drive differentiation of goblet cells in the colonic epithelium. Altogether these findings highlight the importance of ERβ in protection against colorectal carcinogenesis and provide a clinical and translational potential to use ERβ selective agonists in order to prevent and/or treat CRC.PH.D in Biology, July 201