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Interaction of Phenol Red with Estrogenic and Antiestrogenic Action on Growth of Human Breast Cancer Cells ZR-75-1 and T-47-D

Laboratory of Cellular Endocrinology, Imperial Cancer Research Fund, P. O. Box 123, Lincoln's Inn Fields, London WC2A 3PX, England

Studies reported here confirm that the pH indicator, phenol red, acts as a weak estrogen and reexamine the significance of estrogenic and antiestrogenic effects on growth of the human breast cancer cell lines ZR-75-1 and T-47-D in the absence of phenol red. Removal of phenol red reduces but does not immediately eliminate cell growth in the absence of estradiol. Basal cell growth can be reduced for T-47-D cells and eliminated for ZR-75-1 cells by prior growth in the absence of steroid and phenol red for 3 weeks, demonstrating that estrogens can have long lasting effects on cells in culture (termed "steroid memory") and that there exist both cells which are responsive (T-47-D) and dependent (ZR-75-1) on estradiol for growth. Antiestrogen action in these cell lines is affected by at least four parameters: (a) presence of phenol red; (b) time in culture; (c) cell density; (d) steroid memory effects. At high cell density, antiestrogens suppress phenol red-stimulated activity but have little effect in the absence of phenol red. However, at low cell density in the absence of phenol red, tamoxifen has a biphasic action: initial weak stimulation, later inhibition. trans-Hydroxytamoxifen does not stimulate but inhibition increases with time in culture. Following deprivation for 3 weeks of phenol red and steroid, antiestrogen action on ZR-75-1 cells at low density became much more inhibitory. Such responses to antiestrogens are discussed in relation to possible autocrine/paracrine growth regulation of the cells. Clinical relevance is suggested.

¹ To whom requests for reprints should be addressed.

Received 11/30/87. Revised 3/21/88. Accepted 3/31/88.

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