REGULATION OF ESTROGEN ACTIVITY BY SULFATION IN HUMAN MCF-7 BREAST-CANCER CELLS

Estrogen metabolism is closely associated with the growth, progression , and treatment of breast cancer because many breast cancers are depen dent upon estrogens for both growth and progression. Factors that affe ct the intracellular metabolism of estrogens may be critical in alteri ng the effects of estrogens on breast cancer cells. MCF-7 cells have b een 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 t he inactivation of estrogens via sulfation, and MCF-7 cells do not pos sess 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 express ion vector were compared to control cells transformed with vector only . Sulfation of 20 nM E-2 occurs more rapidly with MCF-7 cells transfor med with EST than with the control cells, thereby rendering E-2 physio logically inactive. Additionally, these EST/MCF-7 cells sulfate 20 nM 17 alpha-ethinylestradiol (EE2) at a rate similar to that for E-2 but sulfate 20 nM diethylstilbestrol (DES) much more slowly; these results correlate with the kinetic characteristics of EST for these steroids. EST/MCF-7 cells require higher concentrations of E-2 to stimulate gro wth than do control MCF-7 cells, hypothetically because EST is inactiv ating E-2 via sulfation, rendering it incapable of binding to the estr ogen receptor (ER). The effects of EE2 are similar to those of E-2 whe reas DES is effective at lower concentrations because it is not inacti vated by EST. Neither control nor EST/MCF-7 cells grow well in the com plete absence of estrogens, as would be expected because MCF-7 cells a re estrogen dependent. However, in medium that has not been treated to remove endogenous estrogens, EST/MCF-7 cells grow more slowly than co ntrol cells, most likely because EST is inactivating the estrogens in the medium, making them ineffective in stimulating growth. EST/MCF-7 c ells possess EST at levels similar to HME cells and are less responsiv e to estrogens than are MCF-7 cells lacking EST. The loss of EST may b e a factor in oncogenesis, which leads to altered estrogen metabolism in breast carcinoma cells.