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Proliferation, Hormonal Responsiveness, and Estrogen Receptor Content of MCF-7 Human Breast Cancer Cells Grown in the Short-Term and Long-Term Absence of Estrogens¹

Department of Physiology and Biophysics, University of Illinois, and University of Illinois College of Medicine, Urbana, Illinois 61801

We have examined the effect of short-term and long-term growth in the absence of estrogens on the proliferation rate and estrogen and antiestrogen responsiveness of MCF-7 human breast cancer cells. The removal of phenol red, the pH indicator in tissue culture medium that is weakly estrogenic (Y. Berthois et al., Proc. Natl. Acad. Sci. USA, 83: 2496–2500, 1986), immediately slows the cell proliferation rate, and MCF-7 cells grown in phenol red-free medium with charcoal dextrantreated serum for periods up to 1 mo maintain this reduced rate of cell proliferation. In these short-term phenol red-withdrawn cells, estradiol stimulates proliferation markedly and reproducibly, and antiestrogens inhibit estrogen-stimulated proliferation. Antiestrogens by themselves appear as partial agonists/antagonists; at low concentrations they stimulate proliferation weakly, but they show no stimulation at the high concentrations where they fully inhibit estrogen-stimulated proliferation. In contrast to the short-term phenol red-withdrawn cells, cells maintained for several months (5 to 6 mo) in the apparently complete absence of estrogens (no phenol red, with charcoal dextran-treated calf serum) show a markedly increased basal rate of cell proliferation; estradiol is unable to increase this rate of proliferation further, but antiestrogens are able to decrease proliferation. This change in growth pattern is associated with a 3-fold increase in cellular estrogen receptor levels. Despite their differing basal growth rates, cells grown in either the short-term (<1 mo) or long-term (>6 mo) absence of estrogens both have progesterone receptor levels that are very low and, in both cases, estradiol increases progesterone receptor levels markedly. Thus, under long-term estrogen-free conditions, there is a dissociation between the stimulation of cell proliferation and of specific protein synthesis (progesterone receptor) by estrogen. The increase in the cell proliferation rate observed in cells grown in the long-term absence of estrogen may reflect altered regulation of growth factor production or altered sensitivity to growth factors in the medium or produced by the cells themselves. Hence, these breast cancer cells adapt significantly to long-term growth in estrogen-free conditions, an observation that may be relevant to understanding the growth of hormone-responsive human breast cancers in vivo.

¹ Supported by NIH Grants CA18119 and HD21524. Part of this work was presented at the UCLA Symposium on Steroid Hormone Action, January 1987 (40).

² To whom requests for reprints should be addressed, at Department of Physiology and Biophysics, 524 Burrill Hall, University of Illinois, 407 South Goodwin Avenue, Urbana, IL 61801.

³ Supported in part by a grant from Institut National de la Santé et de la Recherche Médicale. Present address: Laboratoire Cancerologie Experimental, Faculte Medecine Secteur Nord, Boulevard Pierre Dramard, Marseille, France.

Received 3/ 5/87. Revised 5/19/87. Accepted 5/27/87.

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