Prolactin Binds to Human Endometrial Fibroblasts and Inhibits Mitogenicity of an Endometrial Carcinoma Extract

Abstract

Uterine endometrial carcinoma has been reported to synthesize and secrete a putative peptide mitogen that elicits a potent proliferative response in endometrial fibroblasts. The extract from endometrial carcinoma stimulated [3H]thymidine incorporation into human endometrial fibroblasts in a dose-dependent manner. Concomitant exposure of the fibroblasts to prolactin (PRL) led to a remarkable inhibition of the extract-stimulated mitogenic activity of the fibroblasts. This inhibition was dependent on PRL dose, and maximal effect occurred at 1 μM of PRL. PRL (10 nM) suppressed an apparent maximal activity of the extract by 50%, and the half-maximal stimulated effect of the extract on thymidine incorporation was observed at the same concentration in the absence or presence of PRL. This noncompetitive manner may imply that PRL acts at a stage after the interaction of the mitogen in the extract with the specific receptor for mitogen. When the fibroblasts were first exposed to the extract for 12 hr and then to PRL, PRL suppressed the mitogenic activity with no lag. The rapid growth-inhibitory effect of PRL was mimicked by prostaglandin E1, but the combination of both types of ligand was not additive in the inhibitory action on growth. PRLand prostaglandin E₁ may inhibit a similar mitogenic signaling cascade.

Specific receptor sites for PRL were detected in the endometrial fibroblasts, showing high binding affinity (K_d =16.1 nM) and low binding capacity (B_max = 1.59 pmol/mg protein). Treatment of the fibroblasts with the endometrial carcinoma extract induced no changes in the level of PRLreceptor, excluding the possibility that PRL competes for the binding sites with the mitogen. These findings would suggest that PRL may block the mitogenic activity of the fibroblasts stimulated by the endometrial carcinoma-derived mitogen via a PRL receptor-mediated mechanism, perhaps prostaglandin production.