Persistent estrogen responsiveness of ras oncogene-transformed mouse mammary epithelial cells

Abstract

Ovarian steroids are associated with the proliferation of normal as well as tumorigenically transformed mammary epithelial cells. The experiments performed in this study were designed to establish that (1) tumorigenic transformation induced by the ras oncogene is associated with alterations in estradiol biotransformation, (2) altered endocrine responsiveness persists in the fully transformed tumor cell phenotype and (3) specific perturbations induced by the ras oncogene can be experimentally downregulated. The ras transfectant pH06T and the tumor-derived T 1/Pr 1 cells exhibited 3- and 43-fold increases, respectively, in C-16α hydroxylation of estradiol relative to the parental mouse mammary epithelial cells (P < 0.0001). At the cellular level, this alteration corresponded with approximately 90-fold increase in the anchorage-independent growth of T 1/Pr 1 cells (P < 0.0001). Estrogen responsiveness of T 1/Pr 1 cells was demonstrated by their suppression of growth in phenol red-free and/or tamoxifen-supplemented medium and by the reversal of antiproliferative effect of tamoxifen by phenol red and estradiol. Indole-3-carbinol, a naturally occurring tumor suppressive agent, was able to upregulate C-2 hydroxylation at the expense of C-16α hydroxylation of estradiol. Treatment of T 1/Pr 1 cells with indole-3-carbinol resulted in a substantial decrease in anchorage-independent growth. (Steroids 57:262–268, 1992)