Hormone action is mediated by specific cell receptors, resulting in a variety of metabolic responses and/or growth. A number of hormones are implicated in the etiology and growth of mammary cancer. Our studies are directed towards elucidation of the roles of estrogens and antiestrogens, insulin and insulin-like growth factors (IGFS) as regulators of neoplastic growth. By utilizing well characterized rodent models, in vivo and in vitro, experiments are designed to gain understanding of these regulatory actions.
Mechanism of action of estrogens and antiestrogens is being studied by defining the nucleotide requirements for binding of estrogen and antiestrogen activated estrogen receptor with their DNA regulatory element (ERE) and by transfection assays. Estrogen response depends on the expression level of one or both estrogen receptor (ER) isoforms, alpha and beta, and the concentration and type of ER-ligands. Our goal is to understand how these factors contribute to the level of induction characteristic of a particular gene. We have now established that insulin affects tumor growth and regulation, both directly and in a permissive role. We have examined insulin and estrogen receptors, how they are regulated by hormones and how such regulation relates to changes in tumor growth behavior.
A second active area of study is to define the mechanisms whereby tumor cytotoxicity ensues photoradiation therapy, a treatment approach that employs hematoporphyrin photosensitizers followed by exposure of tumors to visible light. The singlet oxygen produced is cytotoxic. We reported that important cellular targets are several mitochondrial respiratory enzymes, leading to reduced ATP production. Current aims are to elucidate these actions and to evolve methods to optimize therapeutic efficacy. The role of estrogenic and antiestrogenic agents in altering production of protoporphyrin IX from 5-aminolevulinic acid and the actions of new synthetic prophyrin derivatives are ongoing projects aimed at improving PDT outcome.