Cellular and molecular events in loss of estrogen sensitivity in ZR-75-1 and T-47-D human breast cancer cells.
When deprived of steroid in the long term, both estrogen-dependent (ZR-75-1) and estrogen-responsive (T-47-D) human breast cancer cells lose estrogen regulation of cell growth in a reproducible time course using both stock lines and recloned cells. The estrogen-stimulated growth rate was unaffected by such treatment, but there was an increase in the basal growth rate without steroid. For ZR-75-1 cells, the effects are clonal but occur at high frequency (1 in 1000 cells) and synchronously between clones, suggesting a phenotypic mechanism. These changes in cell growth occur without any coordinated loss of estrogen sensitivity of molecular markers (pS2 mRNA, progesterone receptor protein) showing that functional estrogen receptors remain present throughout. The constitutive expression of progesterone receptor in one clone of steroid-deprived ZR-75-1 cells does suggest, however, that alterations in expression of individual estrogen-sensitive genes can occur. Loss of estrogen-stimulated growth was not accompanied by loss of growth inhibition by antiestrogen, and the latter effect remained reversible by estradiol. In an attempt to understand the molecular mechanisms underlying the loss of steroid sensitivity in the two cell lines, growth factor gene expression was investigated. Progression to steroid autonomy in T-47-D cells was accompanied by an upregulation of transforming growth factor (TGF) alpha, TGF beta 1, and TGF beta 2 mRNA. However, TGF beta 1 mRNA was downregulated in two ZR-75-1 steroid-deprived clones. These findings are discussed in relation to possible autocrine mechanisms in the loss of steroid sensitivity of breast cancer cells.
Daly
R J
RJ
Cellular Endocrinology Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, England.
Darbre
P D
PD
D001943:Breast Neoplasms / Q000473:pathology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D011506:Proteins; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology; D015291:Transforming Growth Factors / Q000235:genetics; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D004967:Estrogens; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D007335:Insulin-Like Growth Factor II; D015291:Transforming Growth Factors