Correspondence

Mutated Androgen Receptors of Prostate-Cancer Cells

N Engl J Med 1995; 333:1010-1011October 12, 1995

Article

To the Editor:

The study by Taplin and colleagues (May 25 issue)1 provides strong evidence supporting the role of mutant androgen receptors in the emergence of prostate cancer refractory to hormone treatment. We were surprised, however, that these investigators tested the function of the mutated androgen receptors only with estradiol and progesterone. Although stimulation of mutant androgen receptors by these steroids may prove to be of clinical importance, we think that possible functional effects of antiandrogens (such as hydroxyflutamide and bicalutamide) and weak adrenal androgens (such as androstenedione and dehydroepiandrosterone) on mutated androgen receptors are more relevant.

We have hypothesized that mutations in the androgen receptors give insight into the development of hormone-refractory prostate cancer.2 With mutant androgen receptors, hydroxyflutamide can shift from an antagonist to an agonist and adrenal androgens can become potent activators of transcriptional activity.3,4 These findings may explain the progression of prostate cancer in some patients after initial hormonal therapy. They may also explain the effect of flutamide withdrawal, particularly in patients with suppressed testicular and adrenal androgen production.2 The fact that bicalutamide continues to antagonize androgen-stimulated cell growth in cells expressing mutant androgen receptors5 may have important clinical implications. We suspect that a combination of castration and treatment alternating flutamide with bicalutamide may be more efficacious than regimens that include either agent alone.

William D. Figg, Pharm.D.
Matthew Middleman
National Cancer Institute, Bethesda, MD 20892

Oliver Sartor, M.D.
Louisiana State University, Shreveport, LA 71130

5 References

1. 1

   Taplin M-E, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995;332:1393-1398
   Full Text | Web of Science | Medline

2. 2

   Sartor O, Cooper M, Weinberger M, et al. Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of “hormone refractory“ prostate cancer. J Natl Cancer Inst 1994;86:222-227
   CrossRef | Web of Science | Medline

3. 3

   Veldscholte J, Ris-Stalpers C, Kuiper GG, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCap cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 1990;173:534-540
   CrossRef | Web of Science | Medline

4. 4

   Culig Z, Hobisch A, Cronauer MV, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol 1993;12:1541-1550
   CrossRef | Web of Science

5. 5

   Figg WD, McCall NA, Reed E, Sartor AO. The in vitro response of four antisteroid receptor agents on the hormone-responsive prostate cancer cell line LNCaP. Oncol Rep 1995;2:295-298
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The results of our functional studies should not be interpreted to mean that stimulation of mutant androgen receptors by estrogen or progesterone causes the emergence of androgen-independent prostate cancer. Rather, the response to these hormones served primarily to demonstrate that the mutations alter the hormone specificity of the androgen receptor. In response to the question raised by Figg et al., we found that the mutant androgen receptors we analyzed could be activated by hydroxyflutamide and androstenedione (unpublished data). It is of interest that neither patient from whom the mutant androgen receptors were derived had received hydroxyflutamide. Further work will be required to determine whether particular steroid hormones drive prostate-cancer cells with mutant androgen receptors in vivo.

We emphasize that the in vitro assays we and other groups use to study androgen-receptor function in prostate cancer have limitations. Most assays measure only the transcriptional activity of the amino-terminal domain of the androgen receptor, but there is probably transcriptional activity in the (carboxy-terminal) hormone-binding domain that affects prostate-cell growth. The androgen receptor interacts with other cellular proteins, some of which may be prostate-specific. Since only a few human prostate cell lines are available, conclusions from studies of the commonly used LNCaP cell line may be limited. There is thus a need to study the clinical response of patients to additional therapies directed at the androgen receptor, such as ones involving bicalutamide, and to correlate this information with molecular analyses of their tumors.

Steven P. Balk, M.D., Ph.D.
Glenn J. Bubley, M.D.
Todd D. Shuster, M.D.
Beth Israel Hospital, Boston, MA 02215

Citing Articles (1)

Citing Articles

1. 1

   J. Armstrong. (1998) The current status of adjuvant hormonal therapy combined with radiation therapy for localised prostate cancer. Irish Journal of Medical Science 167:3, 138-144
   CrossRef