Cell cycle regulation, apoptosis and estradiol biotransformation: Novel endpoint biomarkers for human breast cancer prevention

Breast cancer is a prevalent disease of the female population in the United States. The multistep process of progression of this organ-site cancer ren ders it preventable by dietary manipulation and/or therapeutic intervention , In vitro explant culture and epithelial cell culture systems established from noncancerous human breast tissue are utilized as mechanistic preclinic al models to examine the process of induction and modulation of carcinogene sis The spectrum of molecular, biochemical, and cellular biomarker assays r epresents specific and sensitive endpoints that provide a measure of quanti tation, Noncancerous target tissue rendered preneoplastic by exposure to ch emical carcinogen or by targeted; expression of oncogenes exhibits aberrant cell cycle progression, down-regulated apoptosis, and altered cellular met abolism of estradiol in vitro prior to tumorigenesis upon orthotransplantat ion into athymic mice in vivo, Altered immunoreactive status of specific re gulatory gene products such as tyrosine kinase,cyclin dependent kinase inhi bitor p16(INK4), and apoptosis specific Bcl-2/Bax provide mechanistic endpo ints. Measurement of cellular metabolism of 17-beta estradiol (E-2) leading to the formation of multiple metabolites with distinct biological properti es provides a marker for endocrine responsiveness, Treatment of preneoplast ic cell type with mechanistically distinct classes of naturally occurring c hemopreventive agents results in down-regulation of perturbed biomarkers. T he present approach validates a high throughput preclinical mechanistic scr een to identify and evaluate novel agents for human breast cancer preventio n.