A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis
Abstract
The purpose of the CoE is to discover the mechanism(s) of estrogen-induced apoptosis in advanced antihormone-resistant breast cancers using our unique models, and to establish the clinical value of short-term low-dose estrogen to reverse antihormone resistance in patients exhaustively treated with antihormone therapy. The clinical trial has begun enrolling patients, but enrollment has been low. We have addressed this by amending patient eligibility and expanding trial site locations. We have completed gene expression microarray hybridizations covering extended E2-treatment time courses of wild-type MCF-7:WS8, and of estrogen deprivation-resistant MCF-7:5C and MCF-7:2A cells, which undergo E2-induced apoptosis. Multiple custom methods have been developed for analyses of time-course microarray data. We have also conducted proteomic analyses, and identified proteins which differentially co-immunoprecipitate with the co-activator AIB1 or phospho-tyrosine complexes in an E2-dependent manner. Using the gene expression microarray and proteomic data, networks were built that highlight differential growth versus apoptosis pathways regulated by E2. Further, based on the microarray analyses, we investigated the G protein coupled-receptor GPR30, and the endoplasmic reticulum stress-associated factors caspase-4 and XBP1 in E2-induced growth or apoptosis. Finally, we surprisingly found that long-term treatment of MCF-7:5C cells with the c-Src inhibitor PP2 reversed E2-induced apoptosis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2009
- Accession Number
- ADA518016
Entities
People
- Virgil C. Jordan
Organizations
- Fox Chase Cancer Center