ESTROGEN PRODUCTION VIA THE AROMATASE ENZYME IN BREAST-CARCINOMA - WHICH CELL-TYPE IS RESPONSIBLE

Studies of breast tumor homogenates from women with breast cancer have demonstrated the synthesis of estrogens in situ through the enzyme ar omatase. The present series of investigations sought to determine whic h cell type within the tumor is responsible for local estrogen biosynt hesis, and whether or not the amount produced is biologically importan t. Accordingly, we utilized an indirect immunohistochemical scoring me thod (H-score) to determine the relative amount of enzyme present in t umor epithelial and stromal cells. This revealed a value of 13 for tum or stromal cells and 4.8 for the epithelial component. Contributing to this difference is the fact that a greater percentage of cells in the tumor were stromal (45%) than epithelial (37%). To obtain direct evid ence that tumor stromal cells could synthesize estrogens, we isolated and grew these cells in tissue culture. Stromal cells originating from within the tumor could be stimulated by known enhancers of transcript ion to produce nearly as much aromatase as is found in placental micro somes. Stromal cells isolated from benign tissue distal to the tumor e xhibited properties similar to those of the tumor stroma. Epithelial c ells, in contrast, did not respond to these enhancers and had low leve ls of aromatase basally. To obtain proof of the principle that local e strogen synthesis can be biologically meaningful, we measured tumor ti ssue estradiol levels and growth rates in aromatase-transfected MCF-7 cells implanted into nude mice. Local synthesis resulted in tumor leve ls ranging from 300 to 800 pg/g and growth rates substantially higher than in non-aromatase-containing tumors. These data suggest that tumor stromal cells contribute the major portion of estrogen synthesized in tumors, and that this local synthesis can increase tumor estradiol le vels and growth rates. (C) 1997 Elsevier Science Ltd.