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

Endocrine therapy for steroid-sensitive tumours often involves adminis tration of steroid antagonists which are designed to bind to the stero id receptor and block steroid action. However, the clinical problem re mains the temporary nature of the tumour regression. Since in vitro mo dels suggest that steroid ablation itself can result in loss of steroi d sensitivity of tumour cells, these studies aimed to investigate the influence of the antiandrogen ICI 141,307 on this progression. This an tiandrogen exhibits both agonist and antagonist actions on androgen-re gulated 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-re ceptor complex can not only bind to the steroid response element (SRE) in the MMTV DNA sequences but also activate gene transcription. Despi te these molecular abilities of this antiandrogen, it was still unable to maintain androgen sensitivity in the long term. It was able to del ay progression to insensitivity of the various steroid-regulated param eters, although the different parameters were delayed for different le ngths of time, but ultimately the antiandrogen was unable to prevent l oss of any parameters. It is thus concluded that the nature of the lig and is critical for maintenance of steroid sensitivity: only androgen and not antiandrogen will maintain long-term response. Previous molecu lar models for loss of steroid response suggest that it could result f rom inactivation of SRE in the genome when no receptor complex is boun d. However, loss of response occurred in these experiments even in the presence of an activated receptor complex capable of binding to the S RE. Possible molecular mechanisms and the clinical implications are di scussed.