Dissertation Defense: John Psaltis
Candidate: John Psaltis
Major: Tumor Biology
Thesis Advisor: Mary Beth Martin, Ph.D.
Title: The Role of Cadmium in the Role the Activation of the Estrogen Receptor Alpha and Endocrine Resistance
The estrogen receptor alpha (ER) plays a central role in the etiology, progression, and treatment of hormone dependent breast cancers. Constitutively activating somatic mutations in the ESR1 (estrogen receptor alpha (ER)) gene ligand binding domain (LBD) represent established mechanisms of acquired resistance to endocrine therapies. This study shows that the metalloestrogen cadmium activates ER through a mechanism similar to calcium and contributes to, and further increases, the constitutive activity of ER mutants Y537S and D538G. Mutational analysis identified the amino acids C381A, N532A, H516A, N519A, E523A, and E542A/D545A as possible calcium/metal interaction sites in the ligand binding domain of the receptor. Mutation of calcium/metal interaction sites C381, N532A, H516A/N519A/E523A, and E542/D545A in Y537S and D538G led to a significant decrease in basal constitutive activity and in the cadmium induced increase in activity. Although mutation of calcium/metal interaction sites in Y537S and D538G did not inhibit DNA binding to the enhancers of estrogen responsive genes, it prevented the stable interaction with SRC1 and PolII. As cadmium activates ER through the solvent accessible surface of the LBD, it enhances the constitutive activity of Y537S and D538G whereas estradiol does not. Taken together, the results suggest that exposure to cadmium plays a role in the etiology, progression, and treatment response of breast cancer due, in part, to its ability to activate ER . As cadmium mimics calcium, the results support further investigation into the inclusion of calcium channel blockers with existing therapies to treat ER-positive metastatic breast cancers.