Androgen receptor alterations in patients with disturbances in male sexual development and in prostatic carcinoma.

The androgen receptor, a ligand-activated nuclear transcription factor belonging to the large superfamily of nuclear receptors, mediates the intracellular action of androgens. It plays a central role in male sexual development and in prostatic carcinoma as a target of endocrine therapy. We have looked for androgen receptor mutations as a cause of male sexual ambiguity and as a possible reason for failure of androgen ablation therapy on prostatic carcinoma.

Androgen receptor alterations in prostatic carcinoma.

Intracellular action of androgens is mediated by the androgen receptor (AR), which is a key element of the androgen signal transduction cascade and a target of endocrine therapy for prostatic carcinoma. Therefore, the qualitative and quantitative alterations of AR expression in prostatic carcinomas and their possible implications for tumor progression and treatment are of great interest. Findings in prostatic tumor cell lines of rat and human origin suggest a reduction of AR protein expression accompanied by an increase in tumor malignancy.

Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor.

Aberrant activation of the androgen receptor (AR) may be one of the mechanisms which contribute to progression of prostatic carcinoma to an androgen-independent stage. We investigated effects of growth factors on stimulation of the AR-mediated gene transcription in human prostatic tumor cell lines. DU-145 cells, which do not contain endogenous AR, were cotransfected with an androgen-inducible chloramphenicol acetyltransferase (CAT) reporter gene and an AR expression vector.

Androgen signal transduction and prostatic carcinoma.

In the prostate, androgen action affects the growth of the gland, its morphology, and regulation of protein expression. Endocrine therapy of non-organ-confined tumors is based on the androgen dependence of the vast majority of prostatic carcinomas. Although initial response rates are high, this therapy is only temporarily effective.

Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone.

Structural changes of the androgen receptor (AR) may contribute to the development of resistance to endocrine therapy in prostatic carcinoma. We have isolated AR cDNA fragments from seven tumor specimens derived from patients with advanced metastatic prostatic tumors. In one specimen obtained from a patient who failed to respond to endocrine and cytotoxic therapy we have detected a point mutation in the hormone-binding domain of the receptor.

DNA sequence of the androgen receptor in prostatic tumor cell lines and tissue specimens assessed by means of the polymerase chain reaction.

Essentially all prostatic carcinomas relapse to an androgen-independent stage during androgen ablation therapy. The underlying genetic changes are still unclear. Such changes are suspected to affect the androgen-signalling pathway as well as growth promoting and inhibiting factors.

Unoccupied prolactin binding components of the benign and malignant human prostate in a subclinical and clinical procedure.

Optimal conditions for the quantitation of free prolactin binding components of human prostatic tissue obtained by TURP were studied by applying gamma receptor assay. The radioligand used was 125I-prolactin. Significantly greater heat stability of the prostate membrane prolactin binding sites, when compared to that of androgen cytoplasmic receptors, was confirmed.