ANTIESTROGENS - MECHANISMS OF ACTION AND RESISTANCE IN BREAST-CANCER

Antiestrogens have proven to be highly effective in the treatment of h ormone-responsive breast cancer. However, resistance to antiestrogen t herapy often develops. In addition, although tamoxifen-like antiestrog ens are largely inhibitory and function as estrogen antagonists in bre ast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective antiestrogens, i.e. compound s that are antiestrogenic on breast and uterus while maintaining the b eneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure -estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel. signal transd uction pathways that impact on the ER. Recent findings show that antie strogens, which are known to exert most of their effects through the E R of breast cancer cells, contact a different set of amino acids in th e hormone binding domain of the ER than those contacted by estrogen, a nd evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pat hway. Resistance could arise in at least four ways: (1) ER loss or mut ation; (2) Post-receptor alterations including changes in cAMP and pho sphorylation pathways, or changes in coregulator and transcription fac tor interactions that affect the transcriptional activity of the ER; ( 3) Changes in growth factor production/sensitivity or paracrine cell-c ell interactions; or (4) Pharmacological changes in the antiestrogen i tself, including altered uptake and retention or metabolism of the ant iestrogen. Model cell systems have been developed to study changes tha t accompany and define the antiestrogen resistant versus sensitive bre ast cancer phenotype. This information should lead to the development of antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become re sistant to a different category of antiestrogens.