Upon binding their cognate receptors, ERα (ESR1) and ERβ (ESR2),
estrogens activate intracellular signaling cascades that have important consequences for cellular behavior. Historically linked to
carcinogenesis in reproductive organs,
estrogens have also been implicated in the pathogenesis of different
cancer types of non-reproductive tissues including the colon. ERβ is the predominant
estrogen receptor expressed in both normal and malignant colonic epithelium. However, during
colon cancer progression, ERβ expression is lost, suggesting that
estrogen signaling may play a role in
disease progression.
Estrogens may in fact exert an anti-
tumor effect through selective activation of pro-apoptotic signaling mediated by ERβ, inhibition of inflammatory signals and modulation of the tumor microenvironment. In this review, we analyze the
estrogen pathway as a possible therapeutic avenue in
colorectal cancer, we report the most recent experimental evidence to explain the cellular and molecular mechanisms of
estrogen-mediated protection against colorectal
tumorigenesis, and we discuss future challenges and potential avenues for targeted
therapy.