The relationship of androgen receptor levels to androgen responsiveness in the Dunning R3327 rat prostate tumor sublines

Abstract

The objective of this study was to determine whether androgen receptor levels in a transplantable animal model of prostatic adenocarcinoma correlated with androgen responsiveness of the tumor. This is the first comparative study of androgen receptor levels in 3 subcellular compartments (cytosol, nuclear salt-extractable and nuclear salt-resistant fractions) of 4 Dunning R3327 rat prostatic adenocarcinoma sublines that vary in their response to androgen ablation. Tumors were harvested from intact adult male rats in order to best approximate the human clinical setting in which receptor levels are quantitated prior to androgen ablative therapy. Only the nuclear salt-resistant (nuclear matrix) and total nuclear androgen receptor contents were significantly different among all tumor sublines. The properties of the tumors studied and their nuclear salt-resistant androgen receptor levels were as follows: H tumor--well-differentiated, slow growing, androgen-dependent, 63 +/- 11 fmol./mg. DNA; HI tumor--well-differentiated, slow growing, androgen-insensitive, 19 +/- 8 fmol./mg. DNA; G tumor--poorly-differentiated, fast growing, androgen-sensitive, 195 +/- 42 fmol./mg. DNA; and AT-2 tumor--anaplastic, fast growing, androgen-insensitive, no detectable receptors. There was no apparent quantitative relationship between androgen receptor content and tumor growth rates, which varied considerably irrespective of the androgen responsiveness of the tumor. However, there was a qualitative relationship between nuclear salt-resistant or total nuclear receptor content and androgen responsiveness. Higher levels of receptor (H and G tumor sublines) were associated with responsiveness to androgen ablation (cessation or slowing of growth, respectively), whereas lower levels of receptor (HI and AT-2 sublines) were associated with androgen insensitivity. These observations, based on relatively homogeneous tumors, may have important implications for human prostatic cancers which appear to be composed of heterogeneous cell populations.