New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis.

摘要

The purpose of the CoE is to discover the molecular mechanisms and the modulation estrogen-induced apoptosis. The laboratory research project is focused on genomics and proteomics with a current focus on molecular interrogation to decipher mechanisms that may be applied to aid patient treatment. In parallel, but not supported by the CoE, is a pilot clinical study of estrogen-induced apoptosis in patients with metastatic breast cancer, that have had repeated cycles of successful antihormone therapy, but have subsequently failed and relapsed. A new low dose protocol is being completed. The molecular pharmacology laboratory of the Principle Investigator (PI) is advancing in all areas originally designated in the grant, e.g. a description of the time dependent changes in estrogen-responsive growth and apoptosis in model cell lines, an evaluation and description of the early proteomic pathways associated with estrogen-induced apoptosis dependent on the estrogen receptor (ER) co-activator AIB1 (SRC-3), the critical importance of the shape of the ER complex, the mechanism of c-Src activity that mediates apoptosis and the genomic spectrum of our endocrine resistant cell lines to define cell sensitivity to estrogen-induced apoptosis. We have discovered and described all the stages of the development of estrogen induced apoptosis through the (mitochondrial) pathway that becomes reinforced by the extrinsic (death receptor) pathway. We have correlated rises in reactive oxygen species (ROS) with intrinsic apoptosis and through RNAseq analysis, identified AP-1 (cFos and cJun) as the critical mediators for estrogen-induced apoptosis.