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Reduction of Estrogen Receptor Concentration in MCF-7 Human Breast Carcinoma Cells following Exposure to Chemotherapeutic Drugs¹

Department of Internal Medicine, Section of Endocrinology, The University of Texas, M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030

To study the effects of commonly used chemotherapeutic drugs on estrogen receptor (ER) of human breast cancer, we investigated the specific binding of [³H]estradiol within intact MCF-7 human breast cancer cells after 1 to 4 hr of exposure to methotrexate (0.5 to 50 µg/ml), 5-fluorouracil, and vincristine in serum- and hormone-free medium. Intracellular [³H]estradiol binding was either slightly increased (methotrexate and 5-fluorouracil) or not changed (vincristine) during the first 2 hr of drug exposures at 37°, but slightly decreased at the third hr. After 4 hr of drug treatments, [³H]estradiol binding within MCF-7 cells was reduced by 30 to 70%; the response was dose dependent. Most (80 to 83%) of the intracellularly bound [³H]estradiol was found within the nuclei, and the drug-induced reduction of ER was reflected by a depleted nuclear uptake of [³H]estradiol. The Scatchard plot showed a large decrease of receptor number per cell with no apparent alteration in the binding affinity. The reduction of ER was reversible; regeneration of receptors to the control level occurred at either 4 hr (methotrexate and 5-fluorouracil) or 8 hr (vincristine) after removal of these drugs. The restoration was followed by an increase of ER beyond the control level. The dose-dependent depletion of ER by these cytotoxic drugs was also detectable in a second ER-positive cell line, MDA-MB-134. These data indicate that the cytotoxic drugs may cause a dose-dependent, reversible depletion of ER in human breast cancer, and the effect seems to be due to inhibition of receptor synthesis rather than inhibition of the binding of estradiol to its receptors.

¹ Research supported by NIH Grants CA 122712-02 and CA-05831-22 and by a grant from the Nancy Carmichael Fund. A preliminary report of this work was presented at the American Association for Cancer Research Meetings, 1982 (7).

² To whom requests for reprints should be addressed.

Received 9/ 3/82. Accepted 4/21/83.