Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches

SIMPLE SUMMARY: Estrogen is known to drive the growth of estrogen-receptor-positive breast cancers, the most common breast cancer subtype. Drugs that target the estrogen receptor by blocking estrogen signaling are the mainstay of treatment. These drugs include tamoxifen, aromatase inhibitors and selective estrogen receptor degraders. Paradoxically, prior to the introduction of tamoxifen, estrogen was used to treat patients with breast cancer. This review will highlight insights and the molecular mechanisms of action and provide a vision for the clinical application of this counterintuitive therapeutic approach to improve patient outcomes. ABSTRACT: Estrogen receptor (ER)-positive breast cancer is the most common subtype, representing 70–75% of all breast cancers. Several ER-targeted drugs commonly used include the selective estrogen receptor modulator (SERM), tamoxifen (TAM), aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs). Through different mechanisms of action, all three drug classes reduce estrogen receptor signaling. Inevitably, resistance occurs, resulting in disease progression. The counterintuitive action of estrogen to inhibit ER-positive breast cancer was first observed over 80 years ago. High-dose estrogen and diethylstilbestrol (DES) were used to treat metastatic breast cancer accompanied by harsh side effects until the approval of TAM in the 1970s. After the development of TAM, randomized trials comparing TAM to estrogen found similar or slightly inferior efficacy but much better tolerability. After decades of research, it was learned that estrogen induces tumor regression only after a period of long-term estrogen deprivation, and the mechanisms of tumor regression were described. Despite the long history of breast cancer treatment with estrogen, this therapeutic modality is now revitalized due to the development of novel estrogenic compounds with improved side effect profiles, newly discovered predictive biomarkers, the development of non-estrogen small molecules and new combination therapeutic approaches.