Acquired estrogen independence and antiestrogen resistance in breast cancer: estrogen receptor driven phenotypes?
Endocrine-responsive breast tumors appear to follow a predictable pattern of progression from estrogen dependence to estrogen independence, ultimately leading to a phenotype characterized by crossresistance among all endocrine therapies. Cells acquiring a multihormone-resistant phenotype, however, frequently retain expression of the cellular receptors for estrogen (ER) and progesterone (PgR). The proliferation of some of these tumors may be driven by a ligand-independent activation of the remaining steroid hormone receptors. Several intracellular secondary messenger systems can potentially activate ER through altering its pattern of phosphorylation in the absence of estrogens. Emerging evidence suggests that, for many estrogen-regulated genes, both the promoter and cellular contexts are critical factors in regulating their transcription by ER. The cellular context may be important because of the presence/absence of several coregulators of ER function, and this context may be unstable in tumor and some normal cell populations. Thus, the pattern of genes regulated by the transcriptional activities of the ER also may change with time, facilitating the emergence of divergent endocrine-responsive phenotypes. It is this pattern of regulation that may be important for conferring each specific phenotype. The repression or induction of the functionally relevant genes responsible for conferring each of the phenotypic changes represents an estrogen-regulated gene network. These networks will contain genes that are regulated, both directly and indirectly, by the activation of ER. Several growth-regulatory gene networks may exist concurrently, providing a cell with several interrelated pathways for controlling its proliferation. The identity of those estrogen-regulated genes that are responsible, for regulating proliferation remains unknown.
Clarke
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Vincent T. Lombardi Cancer Center, Department of Physiology and Biophysics, Georgetown University Medical School, Washington, DC 20007, USA.
Brünner
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