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Estrogen metabolism is closely associated with the growth, progression, and treatment of breast cancer because many breast cancers are dependent upon estrogens for both growth and progression. Factors that affect the intracellular metabolism of estrogens may be critical in altering the effects of estrogens on breast cancer cells. MCF-7 cells have been used as a model system to study the effects of estrogens on breast cancer cellular growth. Because normal human mammary epithelial (HME) cells contain estrogen sulfotransferase (EST), which is involved in the inactivation of estrogens via sulfation, and MCF-7 cells do not possess this enzyme, the absence of EST may be critical to the growth of MCF-7 cells in the presence of estrogens. To study the effects of EST on cellular growth, MCF-7 cells stably transformed with an EST expression vector were compared to control cells transformed with vector only. Sulfation of 20 nM E2 occurs more rapidly with MCF-7 cells transformed with EST than with the control cells, thereby rendering E2 physiologically inactive. Additionally, these EST/MCF-7 cells sulfate 20 nM 17 alpha-ethinylestradiol (EE2) at a rate similar to that for E2 but sulfate 20 nM diethylstibestrol (DES) much more slowly; these results correlate with the kinetic characteristics of EST for these steroids. EST/MCF-7 cells require higher concentrations of E2 to stimulate growth than do control MCF-7 cells, hypothetically because EST is inactivating E2 via sulfation, rendering it incapable of binding to the estrogen receptor (ER). The effects of EE2 are similar to those of E2 whereas DES is effective at lower concentrations because it is not inactivated by EST. Neither control nor EST/MCF-7 cells grow well in the complete absence of estrogens, as would be expected because MCF-7 cells are estrogen dependent. However, in medium that has not been treated to remove endogenous estrogens, EST/MCF-7 cells grow more slowly than control cells, most likely because EST is inactivating the estrogens in the medium, making them ineffective in stimulating growth. EST/MCF-7 cells possess EST at levels similar to HME cells and are less responsive to estrogens than are MCF-7 cells lacking EST. The loss of EST may be a factor in oncogenesis, which leads to altered estrogen metabolism in breast carcinoma cells. |
