Altered Expression of Intermediate Biomarkers for Mammary Preneoplasia: Relevance to Cancer Chemoprevention
Intermediate biomarkers are molecular, metabolic, endocrine, and cellular end points whose expression precedes the detection of cancer. These end points may predict the chemopreventive efficacy of tumor inhibitors. This study was conducted to validate the relevance of selected molecular, endocrine, and cellular biomarkers for efficacy of prototypic tumor suppressing agents. Mouse mammary epithelial cells were initiated for transformation by chemical carcinogen, Ras oncogene and murine mammary tumor virus. The three initiators exhibited at least a two- to five-fold increase in Ras p21-GTP binding (molecular marker), a two- to six-fold increase in C16α/C2 hydroxylation of estradiol (endocrine marker), and a 30- to 50-fold increase in anchorage-independent growth (cellular marker). Treatment of initiated cells with the highest noncytotoxic closes of polyunsaturated n-3 fatty acids, retinoid, anti-estrogens, and indole derivatives resulted in downregulation of all the three perturbed biomarkers. Enhanced expression of molecular, endocrine, or cellular markers in initiated, tumorigenic target cells, and their in vitro modulation by prototypic tumor suppressing agents demonstrates that the biomarkers provide specific and sensitive end points for evaluating the efficacy of chemopreventive intervention.