Endocrinology, Vol 136, 824-832, Copyright © 1995 by Endocrine Society

ARTICLES

Prolonged treatment of breast cancer cells with antiestrogens increases the activating protein-1-mediated response: involvement of the estrogen receptor

ME Astruc, C Chabret, P Bali, D Gagne and M Pons
INSERM U-58, Montpellier, France.

At micromolar (pharmacological) concentrations, the action of tamoxifen on the proliferation of estrogen-dependent cells can be mediated not only by the estrogen receptor (ER), but also by other target molecules, such as protein kinase-C (PKC), which are easily inhibited by antiestrogens in cell-free experiments. By developing MTLN and MDT cell lines, in which any modulation of PKC activity is reflected by a variation of the expression of an activating protein-1 (AP-1)- controlled firefly luciferase gene, we investigated whether such antiestrogen inhibitory effects on PKC occurred in intact breast cancer cells. Firstly, in short term (4-h) treatment of both cell lines, antiestrogens only inhibited the 12-O-tetradecanoyl-phorbol-13-acetate- induced luciferase activity at very high concentrations (30 microM). A cytolytic effect was also observed. Secondly, in prolonged (4-day) treatments of MTLN (ER-positive) cells, low antiestrogen concentrations (nanomolar) decreased the basal AP-1 response by about 2 and increased the 12-O-tetradecanoyl-phorbol-13-acetate-stimulated AP-1 response by about 3-4. This stimulation was mediated by ER, because 1) dose- response curves established with tamoxifen and hydroxytamoxifen were in agreement with their affinity for ER; 2) when present with antiestrogens, estradiol abolished this phenomenon; and 3) this effect was not observed in MDT (ER-negative) cells. Such a latent activation of AP-1 pathway could appear in the course of breast cancer antiestrogen treatment, in conditions where natural PKC activators are abnormally produced with unexpected consequences on the results of a long term antiestrogen treatment.

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