Estrogen Regulation of Human Breast Cancer Cell Line MCF-7 Tissue Plasminogen Activator*

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Abstract
The human breast cancer cell line MCF-7 produces a number of estrogen-regulated proteins, among which is tissue plasminogen activator (tPA). Increased medium concentrations of PA activity were observed after the addition of 17.beta.-estradiol to cultures of MCF-7 cells. However, in the current study these hormone-regulated increases are limited to cultures near or at confluence, but not in the preconfluent period. MCF-7 cell cultures produce either tPA activity alone or in combination with urokinase activators. At confluence, a single exposure to 17.beta.-estradiol stimulates a marked transitory rise in tPA activity in the extracellular and cell-associated compartments; the peak increases were at 48 h for medium activity and 24-48 h for cell-associated activity. Sustained exposure to hormone leads to a persistent increase in activity in both compartments. Examination of the structure-function relationships of estrogen agonists, steroidal and nonsteroidal, as well as nonestrogenic steroids indicated that stimulation of PA activity was restricted to estrogen agonists. The increased activity was reflected in enhancement of tissue PA activity when viewed using sodium dodecyl sulfate-polyacrylamide gel zymography. Those cultures expressing both activators revealed no alteration of urokinase activity due to hormone addition. Antiestrogens added to MCF-7 cells not rigorously limited in exogenous estrogens selectively suppressed tissue PA activity, but not that of urokinase. These data indicate that at the point when MCF-7 cell cultures are no longer growing exponentially, addition of estrogen agonists at physiological concentrations elevates tPA activity while not altering expression of urokinase activity. The discussion suggests a possible role that this regulation may subserve in the function of breast epithelial cells.