Abstract

The estrogen responsive human breast cancer MCF-7 cell culture was examined for its response to 2-hydroxyestrone a principal metabolite of estradiol. Addition of 2-hydroxyestrone to the cell cultures in concentration of 10(-9) - 10(-6) M had no effect on cell growth and proliferation because of rapid O-methylation of the catechol estrogen by catechol O-methyltransferase which is highly active in these cells. In the presence of quinalizarin, a potent catechol O-methyltransferase inhibitor which reduces the O-methylation of the steroid, 10(-7) M and 10(-8) M 2-hydroxyestrone markedly suppresses the growth and proliferation of the cells. The tumor cell growth-inhibitory action of the catechol estrogen was neutralized by the presence of 10(-9) M estradiol. The catechol estrogen inhibition of cell growth is not observed in the estrogen receptor-negative human breast cancer cell lines MDA-MB-231 and MDA-MB-330 providing evidence that the inhibition is specific and is estrogen receptor-mediated. In contrast, the 16 alpha-hydroxylated metabolites of estradiol, estriol and 16 alpha-hydroxyestrone, are effective stimulators of MCF-7 cell proliferation with the latter exhibiting potency in excess of that expected from its estrogen receptor affinity. The present results represent the first observation of a specific receptor-mediated antiestrogenic action of 2-hydroxyestrone and suggest that the physiological regulation of the agonist activity of the primary estrogen may involve in situ generation of catechol estrogen.

Highlights

  • Addition of 2-hydroxyestrone to the cellcultures in concentration of 10-9-10-6 M had no effect on cell growth and proliferation because of rapid O-methylation of the catechol estrogen by catechol O-methyltransferase which is highly activein these cells.In the presence of quinalizarin, a potent catechol O-methyltransferase inhibitor which reduces the O-methylation of the steroid, lo-’ M and lo-’ M 2-hydroxyestrone markedly suppresses the growth and proliferation of the cells

  • The catechol estrogen inhibition ofcell growth is not observed in the estrogenreceptor-negative human breast cancer cell linesMDA-MB-231 and MDA-MB-330 providing evidence that the inhibition is specific and is estrogen receptor-mediated

  • In the present studywe have used the hormone-dependent human breast cancer cell line MCF-7 in tissue culture as a system for the studyof the biological effects of 2-hydroxyestrone, under conditions where its further metabolism could be controlled, and its activity in peripheral estrogen target sites beevaluated.Our resultsindicatethatthe catechol estrogen behaves as an antiestrogen in suppressing the tumor cell proliferation both under control and estradiol stimulatory conditions

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Summary

Introduction

The estrogen responsive human breast cancer MCF7 cell culture was examined for its response to 2hydroxyestrone a principal metabolite of estradiol.

Results
Conclusion
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