Progestins Induce Down-Regulation of Insulin-Like Growth Factor-I (IGF-I) Receptors in Human Breast Cancer Cells: Potential Autocrine Role of IGF-II

Abstract

Insulin-like growth factor-I (IGF-I) receptors are present in breast cancer cells and may play a role in breast cancer cell growth. We have studied the effect of progestins on IGF-I receptors in T47D human breast cancer cells. T47D cells constitutively express high levels of progesterone receptors and are a model for studying the regulation of cellular functions by progestins. Treatment of T47D cells with either progesterone or the synthetic progestin promegestone (R5020) decreased IGF-I receptor content by approximately 50%, as measured by Scatchard analysis and receptor biosynthesis studies. In contrast to progestins, estradiol, dexamethasone, and dihydrotestosterone did not influence IGF-I receptor content. No effect of R5020 was seen after 12 h of incubation, a near-maximal effect was seen after 24 h, and greatest effects were seen after 72 h. R5020 decreased IGF-I receptor mRNA abundance, indicating that progestins acted at the level of gene expression. However, progestins also increased the secretion of IGF-II, a ligand for the IGF-I receptor. In contrast to IGF-II, T47D cells did not express IGF-I. The addition of exogenous IGF-II to T47D cells down-regulated both IGF-I receptor binding and IGF-I receptor mRNA abundance. This study indicates, therefore, that progestins regulate IGF-I receptors in breast cancer cells and suggests that this regulation occurs via an autocrine pathway involving enhanced IGF-II secretion.

Author notes

This work was supported by the John A. Kerner Foundation; USPHS Grant CA-39825A (to P.K.S.), NICHHD Grant K08- HD-00836 (to S.M.R.); and the Ladies Auxiliary to the Veterans of Foreign Wars, Department of California.

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Present address: Cattedra di Endocrinologia, Università di Catania, Ospedale Garibaldi, Piazza di Gesù, 95123 Catania, Italy.