[Cancer Research 46, 4933-4937, October 1, 1986]
© 1986 American Association for Cancer Research
Stimulation of Cell Proliferation and Estrogenic Response by Adrenal C19-
5-Steroids in the ZR-75-1 Human Breast Cancer Cell Line1
Richard Poulin and
Fernand Labrie2
MRC Group in Molecular Endocrinology, Laval University Medical Center, Quebec G1V 4G2, Canada
We have examined the effect of androst-5-ene-3ß,17ß-diol (
5-diol) and its precursors, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone 3ß-sulfate (DHEAS), on the growth of the estrogen-sensitive human breast cancer cell line, ZR-75-1. While the cell number was increased up to 4-fold by maximal concentrations of estradiol, 5-diol maximally stimulated cell proliferation by approximately 3-fold. Since the half-maximal stimulation achieved by 5-diol is observed at 2.5 nM and the normal range of plasma concentrations of this steroid in women is 1 to 3 nM, it is most likely that the stimulatory effect of 5-diol has physiological significance. DHEA and DHEAS were much less effective than 5-diol in stimulating the proliferation of ZR-75-1 cells, the maximal effect on cell number being 75% at the maximal dose used, namely 10 µM. The mitogenic effects of estradiol and 5-diol were competitively inhibited by the antiestrogen LY156758 (keoxifene), while the effects of DHEA and DHEAS were completely abolished by the antiestrogen. The effects of DHEA and 5-diol on cell proliferation are not likely to be mediated via their conversion to estrone or estradiol, since androstenedione had no effect, while testosterone and dihydrotestosterone decreased cell number by about 20%. The number of specific progesterone binding sites was increased 3.7-, 3.2-, and 2.0-fold by 5-diol, DHEA, and DHEAS, respectively. The relative potency of the C19-5-steroids to increase the number of progesterone-specific binding sites was comparable to their ability to stimulate cell proliferation. Direct competition experiments performed with intact cells in monolayer culture showed that, under conditions of minimal metabolism, only 5-diol could significantly compete with estradiol for cellular estrogen-specific binding sites with an apparent dissociation constant of 11 nM, thus suggesting that physiological concentrations of C19-5-steroids of adrenal origin could exert an estrogenic stimulation of breast tumor growth without involvement of the aromatase pathway. The present data suggest not only that estrone derived from androstenedione could play a role in estrogensensitive breast cancer in women but that 5-diol could well be the most important estrogen in breast cancer in women.
1 Supported by grants from the Medical Research Council of Canada. Parts of this work have been presented at the Annual Meeting of the Canadian Society for Clinical Investigation (1).
2 To whom requests for reprints should be addressed.
Received 3/21/86.
Revised 6/18/86.
Accepted 7/15/86.
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Copyright © 1986 by the American Association for Cancer Research.
