Persistent estrogen responsiveness of ras oncogene-transformed mouse mammary epithelial cells.
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 T1/Pr1 cells exhibited 3- and 43-fold increases, respectively, in C-16 alpha hydroxylation of estradiol relative to the parental mouse mammary epithelial cells (P less than 0.0001). At the cellular level, this alteration corresponded with approximately 90-fold increase in the anchorage-independent growth of T1/Pr1 cells (P less than 0.0001). Estrogen responsiveness of T1/Pr1 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-16 alpha hydroxylation of estradiol. Treatment of T1/Pr1 cells with indole-3-carbinol resulted in a substantial decrease in anchorage-independent growth.
Suto
A
A
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
Bradlow
H L
HL
Wong
G Y
GY
Osborne
M P
MP
Telang
N T
NT
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001711:Biotransformation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D007211:Indoles; D013629:Tamoxifen; D004958:Estradiol; C016517:indole-3-carbinol