AP-1 Activity in Tamoxifen-Resistant Human Breast Tumors
Annual rept. 1 Sep 1999-31 Aug 2000
CALIFORNIA UNIV SAN FRANCISCO
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The hormonal therapy of choice for the treatment of breast cancer has been the antiestrogen tamoxifen. However, tumors eventually acquire a tamoxifen-resistant or tamoxifen-stimulated phenotype, resulting in disease recurrence. Estrogen receptor ER is known to interact with other transcription factors such as AP-l through protein-protein interactions. AP-1 responds to a variety of extracellular signals, including oxidative stress and growth factor stimulation and regulates a variety of genes that could be associated with cellular growth resistant deregulation and transformation. Tamoxifen has been shown to induce oxidative stress and tamoxifen resistant ER positive cell lines are associated with increased AP-1 binding, suggesting that enhanced AP-1 activity can account for tamoxifen- stimulated growth. In this study, I focus on the role of oxidant stress-mediated interactions between ER and AP- 1. 1 have begun development of a novel in vitro transcription and translation assay. I have also begun studying the possible induction of a stress- induced proteasome-ubiquitin ER degradation pathway that may be detectable in human breast tumor samples. Finally, I have completed an initial analysis of 71 breast tumor extracts for key molecular parameters of oxidative stress and growth factor signaling including AP-l DNA binding, Sp1 DNA binding and protein content, and Erk5 activation.
- Anatomy and Physiology
- Medicine and Medical Research