Estrogen Receptors and Enzymes Involved in Estrogen Synthesis as Breast Cancer Treatment Targets

Estrogens, particularly the most active 17β-estradiol (E2), play a crucial role in the initiation and development of breast cancer. Therefore, current treatment strategies are based on interfering with estrogen receptors (ERs) via pure antiestrogens or selective modulators (SERMs) or by inhibiting estrogen synthesis through key enzymes in this pathway. While SERMs are generally effective, resistance often develops. Moreover, they cannot be used to treat triple-negative breast cancers (TNBCs). Three critical enzymes in the estrogen synthesis pathway, namely aromatase, sulfatase, and 17β-hydroxysteroid dehydrogenases, are of particular interest as drug targets. Some, such as aromatase inhibitors, are already used in clinical practice, while the other two remain under intensive investigation. Several comprehensive reviews have been published on ER modulators or individual enzyme inhibitors. This paper attempts to summarize recent data on modulators/inhibitors of both the ER and the major enzymes involved in estrogen biosynthesis and offers a perspective on their further development.