Reversibility of pre-malignant estrogen-induced epigenetic changes

The development of early detection and prevention strategies of breast cancer relies on defining molecular and cellular events that characterize progressive alterations underlying preneoplastic changes in the mammary epithelium. Studies have shown that estrogen exerts its carcinogenic effects through both genetic and epigenetic pathways to promote imbalances in proliferation and apoptosis, genomic instability and cancer. The purpose of this study was to identify the earliest epigenetic changes that could be detected in response to estrogen treatment. More importantly, having detected these early pre-malignant epigenetic changes, a follow-up study was designed to address the potential to reverse these estrogen-induced alterations. Using a well-established ACI rat model, morphological and epigenetic changes were identified in the mammary gland tissue as early as 2 days after exposure to constitutively elevated estrogen levels produced by continuous release estrogen mini-pellets. Progressive hyperproliferative changes were paralleled by epigenetic disturbances, including the upregulation of DNA methyltransferases and hyperacetylation of histone residues. These changes could be detected early, and they continued to persist if estrogen was maintained within a high physiological range. Epigenetic features of short-term estrogen exposure were strikingly similar to hallmarks of cancer promotion and progression. Yet, importantly, these changes exhibited a degree of reversibility if a source of elevated levels of estrogen was removed. Knowing that operational reversibility during the promotion stage of carcinogenesis provides a window for intervention, the potential to reverse the effects of elevated levels of estrogen prior to tumor development may prove to be a promising avenue to explore.