A Unique Breast Cancer Cell Model for Studying Reported Functions of Membrane-Localized Estrogen Receptor
Final rept. 1 Apr 2002-31 Mar 2006
BAYLOR COLL OF MEDICINE HOUSTON TX
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We have generated ER-negative breast cancer cell lines C4-12 that express ERalpha only in the cytoplasm cERalpha - deletion of the nuclear localization sequence to characterize the putative cytoplasmic functions of ERalpha. As expected, estrogen stimulation of C4-12-cERalpha didnt stimulate genomic ER activity. However, estrogen also failed to increase growth of these cells and didnt stimulate non-genomic ER signaling via ERK12 or Akt. Interestingly, however, we found that estradiol stimulated cERalpha was degraded by the proteasome challenging the notion that transcription and degradation are linked, and also found that cERalpha was completely resistant to ICI182780-mediated degradation. We have generated C4-12 cells expressing ERalpha exclusively in the plasma membrane chimeric protein of rhodopsin fused to full length ERalpha and including the NLS and found that estrogen is able to rapidly activate ERK12 in these cells. Rho-ER is degraded by estrogen and ICI, directly implicating the NLS of ER in ICI-mediated degradation. These studies do not support a major role for cytoplasmic ER in non-genomic ER signaling, however they clearly illustrate significant differences between estrogen and ICI-mediated ERalpha degradation.
- Medicine and Medical Research