Factors Modulating Estrogen Receptor Activity.
Annual rept. 1 Jul 97-30 Jun 98
NEW YORK UNIV MEDICAL CENTER NY
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The mechanism of signal transduction by the estrogen receptor ER, an estrogen-dependent transcription factor that plays a role in the initiation and progression of breast cancer, is complex and not fully understood. In addition to ER, a number of accessory proteins are apparently required to efficiently transduce the steroid hormone signal. In the absence of estradiol, ER, like other steroid receptors, is complexed with Hsp9O and other molecular chaperone components, including an immunophilin, and p23. This Hsp9O-based chaperone complex is thought to repress ERs transcriptional regulatory activities while maintaining the receptor in a conformation that is competent for high affinity steroid binding. However, a role for p23 in ER signal transduction has not been demonstrated. Using a mutant ERG4OOV with decreased hormone binding capacity as a substrate in a dosage suppression screen in yeast S. cerevisiae, we identified the Hsp-90 associated co-chaperone p23 as a positive regulator of ER function in yeast and breast cancer cells. Together, our results strongly suggest that p23 plays an important regulatory role in ER signal transduction and as such, may be exploited in the development of new therapies for estrogen-dependent malignancies, such as breast cancer.
- Anatomy and Physiology
- Medicine and Medical Research