THE OVEREXPRESSION OF INT-5/AROMATASE, A NOVEL MMTV INTEGRATION LOCUS GENE, IS RESPONSIBLE FOR D2 MAMMARY-TUMOR CELL-PROLIFERATION

Our recent studies have shown that the cellular gene at the mouse mammary tumor virus (MMTV) integration site in the int-5 locus in BALB/c D2 precancerous hyperplastic alveolar nodules is identical to the gene encoding aromatase (CYP19), a member of the cytochrome P450 gene superfamily. MMTV integrated within the 3' untranslated region of the aromatase gene is responsible for the overexpression of this gene (int-5/aromatase) in mammary tumors. This paper describes the biological significance of overexpression of int-5/aromatase in D2 tumor cells. Using a cell line derived from the D2 tumor, we have demonstrated the effect of the aromatase substrate, androstenedione, on the proliferation of tumor cells. Proliferative effects of androstenedione were blocked by an aromatase inhibitor, providing evidence for the role of int-5/aromatase in this process. Furthermore, the androstenedione-mediated proliferation was inhibited by the addition of anti-estrogen ICI 164,384, suggesting that the estrogen formed from the conversion of androstenedione by int-5/aromatase acts like a mitogen to stimulate the growth of D2 tumor cells. This model with its known mechanism of aromatase activation should prove useful for studying the role of intra-tumoral estrogen in mammary cancer, for evaluating the effects of aromatase inhibitors, and for comparing breast cancer treatments.