Endocrine therapy is effective in approximately one-third of all breast can
cers and up to 80% of tumors that express both estrogen and progesterone re
ceptors. Despite the low toxicity, good overall response rates, and additio
nal benefits associated with its partial agonist activity, most Tamoxifen-r
esponsive breast cancers acquire resistance. The development of new antiest
rogens, both steroidal and non-steroidal, provides the opportunity for the
development of non-cross-resistant therapies and the identification of addi
tional mechanisms of action and resistance. Drug-specific pharmacologic mec
hanisms may confer a resistance phenotype, reflecting the complexities of b
oth tumor biology/pharmacology and the molecular endocrinology of steroid h
ormone action. However, since all antiestrogens will be effective only in c
ells that express estrogen receptors (ER), many mechanisms will likely be d
irectly related to ER expression and signaling. For example, loss of ER exp
ression/function is likely to confer a cross-resistance phenotype across al
l structural classes of antiestrogens. Altered expression of ER alpha and E
R beta, and/or signaling from transcription complexes driven by these recep
tors, may produce drug-specific resistance phenotypes. We have begun to stu
dy the possible changes in gene expression that may occur as cells acquire
resistance to steroidal and non-steroidal antiestrogens. Our preliminary st
udies implicate the altered expression of several estrogen-regulated genes.
However, resistance to antiestrogens is likely to be a multigene phenomeno
n, involving a network of interrelated signaling pathways. The way in which
this network is adapted by cells may vary among tumors, consistent with th
e existence of a highly plastic and adaptable genotype within breast cancer
cells. (C) 2001 Elsevier Science Ltd. All rights reserved.