Low-Dose Estrogen Therapy to Reverse Acquired Antihormonal Resistance in the Treatment of Breast Cancer

Estrogen is a potent stimulus for growth in its target organs: the uterus, vagina, and some estrogen receptor–positive breast cancers. However, estrogen is also able to control menopausal symptoms and maintain bone density in postmenopausal women. Until recently, there was also believed to be a link between estrogen and the prevention of cardiovascular disease. For these reasons, hormone replacement therapy (HRT) with an orally active estrogen and progesterone has been used routinely for more than 50 years to maintain physiologic homeostasis after menopause. Not surprisingly, HRT increases the risk of developing breast cancer. The link between estrogen and breast cancer growth served as the incentive to develop long-term tamoxifen therapy and, subsequently, the aromatase inhibitors (AIs) as successful “anti-estrogenic” treatments. Unfortunately, the consequence of exhaustive therapy is drug resistance. Laboratory studies have defined the evolution of tumor drug resistance to tamoxifen, raloxifene (used for breast and osteoporosis chemoprevention), and the AIs. Remarkably, the long-term exposure of breast cancers to antihormonal therapy also exposes a vulnerability that is being exploited in the clinic. Years of antihormonal therapy alters the cellular response mechanism to estrogen. Normally, estrogen is classified as a survival signal in breast cancer, but in sensitive antihormone-resistant cells, estrogen induces apoptosis. When resistant cells are killed, antihormonal therapy is once again effective. This new targeted approach to the treatment of metastatic breast cancer could open the door to novel approaches to treatment with drug combinations.