Regulation of MCF-7 breast cancer cell growth by beta-estradiol sulfation.
Estrogen stimulation is an important factor in human breast cancer cell growth and development. Metabolism of beta-estradiol (E2), the major endogenous human estrogen, is important in regulating both the level and activity of the hormone in breast tissues. Conjugation of E2 with a sulfonate moiety is an inactivation process since the sulfate ester formed by this reaction can not bind and activate the estrogen receptor. In human tissues including the breast, estrogen sulfotransferase (EST, SULT1E1) is responsible for high affinity E2 sulfation activity. EST is expressed in human mammary epithelial (HME) cells but not in most cultured breast cancer cell lines, including estrogen responsive MCF-7 cells. Stable expression of EST in MCF-7 cells at levels similar to those detected in HME cells significantly inhibits cell growth at physiologically relevant E2 concentrations. The mechanism of cell growth inhibition involves the abrogation of responses observed in growth factor expression in MCF-7 cells following E2 stimulation. MCF-7 cells expressing EST activity did not show a decrease in estrogen receptor-alpha levels, nor a characteristic increase in progesterone receptor or decrease in transforming growth factor-beta expression upon exposure to 100 pM or 1 nM E2. The lack of response in these MCF-7 cells is apparently due to the rapid sulfation and inactivation of free E2 by EST. These results suggest that loss of EST expression in the transformation of normal breast tissues to breast cancer may be an important factor in increasing the growth responsiveness of preneoplastic or tumor cells to estrogen stimulation.
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 35294, USA.
Josie L
JL
Falany
Nancy
N
Macrina
Charles N
CN
Falany
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015238:Sulfotransferases / Q000096:biosynthesis / Q000494:pharmacology*; D013455:Sulfur / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004958:Estradiol; D013455:Sulfur; D015238:Sulfotransferases; C020122:estrone sulfotransferase