ANTIANDROGEN ACTION IN THE DEVELOPMENT OF ANDROGEN INSENSITIVITY IN S115 MOUSE MAMMARY-TUMOR CELLS

Endocrine therapy for steroid-sensitive tumours often involves administration of steroid antagonists which are designed to bind to the steroid receptor and block steroid action. However, the clinical problem remains the temporary nature of the tumour regression. Since in vitro models suggest that steroid ablation itself can result in loss of steroid sensitivity of tumour cells, these studies aimed to investigate the influence of the antiandrogen ICI 141,307 on this progression. This antiandrogen exhibits both agonist and antagonist actions on androgen-regulated cellular and molecular parameters of S115 mouse mammary tumour cells in culture. Its ability to regulate mouse mammary tumour virus (MMTV) RNA production in these cells confirms that the antiandrogen-receptor complex can not only bind to the steroid response element (SRE) in the MMTV DNA sequences but also activate gene transcription. Despite these molecular abilities of this antiandrogen, it was still unable to maintain androgen sensitivity in the long term. It was able to delay progression to insensitivity of the various steroid-regulated parameters, although the different parameters were delayed for different lengths of time, but ultimately the antiandrogen was unable to prevent loss of any parameters. It is thus concluded that the nature of the ligand is critical for maintenance of steroid sensitivity: only androgen and not antiandrogen will maintain long-term response. Previous molecular models for loss of steroid response suggest that it could result from inactivation of SRE in the genome when no receptor complex is bound. However, loss of response occurred in these experiments even in the presence of an activated receptor complex capable of binding to the SRE. Possible molecular mechanisms and the clinical implications are discussed.