Regulation of androgen receptor gene expression by steroids and retinoic acid in human breast‐cancer cells

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Abstract
Although the androgen receptor (AR) has been detected by ligand‐binding assays, there is little known about the expression and regulation of the AR gene in human breast‐cancer cells. AR mRNA, measured by Northern analysis in 18 cell lines, was found to be expressed predominantly in oestrogen‐ and progesterone‐receptor‐positive (ER+, PR+) lines as a single species of approximately 10.5 kb but was also comparatively abundant in I ER‐ and PR‐negative cell line, MDA‐MB‐453. Dexamethasone (Dex), Organon 2058 (Org 2058), dihydrotestosterone (DHT), and all‐trans‐retinoic acid (RA) down‐regulated AR mRNA levels in T‐47D (ER+, PR+) cells 6 hr after treatment, whereas oestradiol (E2) had no effect. In MDA‐MB‐453 (ER−, PR−) cells, regulation of AR mRNA by RA differed from the other cell lines: RA increased the level of AR mRNA. DHT‐binding assays indicated a corresponding increase in AR protein. Transfection of the androgen‐responsive mouse mammary tumour virus long‐terminal repeat (MMTV LTR) linked to a chloramphenicol acetyltransferase (CAT) reporter gene was used to examine the effect of altered AR levels on androgen action. The increased level of AR following RA pre‐treatment in MDA‐MB‐453 cells resulted in enhanced induction of CAT activity by DHT and, conversely, a decrease in the level of AR following RA pretreatment in T‐47D cells resulted in reduced induction of CAT activity by DHT. These data demonstrate that AR is expressed predominantly in ER+ and PR+ cell lines and its expression is regulated by ligands also known to regulate ER or PR, including progestins and retinoids. Androgen responsiveness measured by a transfected reporter gene was altered according to the extent of up‐ or down‐regulation of AR expression, demonstrating that responsiveness is dependent on receptor concentration.