Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

Abstract

This article describes the origins and evolution of "antiestrogenic" medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer. However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.

Figure 1

The activation of the pro drug tamoxifen to 4-hydroxytamoxifen which has a high binding affinity for ER [103]. This knowledge resulted in the development of numerous new agents for use as selective estrogen ER modulations (SERMs) for the prevention of breast cancer and osteoporosis or the pure antiestrogen fulvestrant used as a treatment for ER positive advanced breast cancer following the failure of either tamoxifen treatment or an aromatase inhibitor.

Figure 2

Aromatase Inactivators: Several steroidal inhibitors have been demonstrated to bind irreversibly or very tightly to the active site of aromatase e.g., 4-hydroxyandrostenedione (4-OHA).

Figure 3

The structures of various aromatase inhibitors tested clinically for the treatment of breast cancer. The compounds are classified based on their mode of action and specificity for the aromatase enzyme.

Figure 4

Aromatase mediates conversion of androgens to estrogens. Three hydroxylation steps are postulated.

Figure 5

Interaction of Non-Steroidal Inhibitors with Aromatase

Figure 6

A diagramatics representation of the estrogen signal transduction pathway. The ligand estrogen receptor (either alpha or beta) (ER) complex is modulated in its actions by coactivators (CoA) or the unoccupied receptor is neutralized by corepressors (CoR). Overall the pathway can be further modified by phosphorylation of the ER or modulator molecules via growth factor receptor signaling pathways at the cell membrane (and membrane bound ER). These phosphorylation pathways are enhanced in antihormone resistance to allow the ER to promote unregulated gene activation through genomic and tethered mechanisms. This aids survival by preventing cancer cell apoptosis. Previously published in [14] and reprinted and adapted with permission.

Figure 7

A Human Breast Cancer Cell Line Stably Transfected with Aromatase is Sensitive to Aromatase Inhibitors and antiestrogens.