The Role of Estrogen and Estrogen Receptors in Chemoresistance

Drug resistance is one of the major obstacles limiting the success of cancer chemotherapy. Biological mechanisms contributing to drug resistance may be present de novo and related to inherent features or may be raised after exposure to anticancer drugs. In recent years, both clinical observations and experimental studies suggested that steroid hormones and their receptors might also affect the therapeutic efficacy of antineoplastic drugs. Estrogens and estrogen receptors (ER) are well-known for their critical roles in the development and progression of breast tumors. It has long been known that breast tumors expressing ER alpha protein (ER alpha+) behave in a fundamentally different fashion than ER alpha-negative (ER alpha-) tumors with regard to their responses to hormonal therapy. Data obtained from both laboratory and clinical investigations suggested that some chemotherapeutic agents are clearly less effective in ER alpha+ tumors than ER alpha-tumors, although the mechanisms of ER alpha-mediated chemoresistance are not entirely clear. Moreover, recent studies from our laboratory and others demonstrated that the combination of antiestrogenic agents with chemotherapeutic drugs is of significant therapeutic benefit in ER alpha+ breast cancer over chemotherapy alone. In addition, the ER alpha-derived peptides, microRNAs specifically targeting ER alpha, as well as agents targeting estrogen-related receptors (ERRs) may hold promise to sensitize ER alpha+ breast tumors to chemotherapy. Considering that ERs are expressed in similar to 65% of human breast cancer, the ER alpha-mediated chemoresistance has become a big challenge for clinical treatment. The hope to overcome this drug resistance relies on further clarification of specific pathways or molecules contributing to the resistance. More exhaustive and systematic studies are essential to reach deeper understandings on the underlying mechanisms and to develop novel approaches to sensitize ER alpha+ breast tumors to chemotherapy.