Decreased Androgen Receptor Levels and Receptor Function in Breast Cancer Contribute to the Failure of Response to Medroxyprogesterone Acetate

Abstract

Previously, we reported that androgen receptor (AR), but not estrogen receptor (ER) or progesterone receptor (PR), is predictive of response to the synthetic progestin, medroxyprogesterone acetate (MPA), in a cohort of 83 patients with metastatic breast cancer. To further investigate the role of AR in determining response to MPA in this cohort, we analyzed AR levels by immunohistochemistry with two discrete antisera directed at either the NH 2 or the COOH termini of the receptor. Compared with tumors that responded to MPA (n = 31), there was a significant decrease in the intensity and extent of AR immunoreactivity with both AR antisera in tumors from nonresponders (n = 52). Whereas only a single AR immunostaining pattern was detected in responders to MPA, reflecting concordance of immunoreactivity with the two AR antisera, tumors from nonresponders exhibited four distinct AR immunostaining patterns: (a) concordance with the two antibodies (31%), (b) staining only with the COOH-terminal antibody (33%), (c) staining only with the NH 2 -terminal antibody (22%), or (d) no immunoreactivity with either NH 2 -or COOH-terminal antibody (14%). DNA sequencing and functional analysis identified inactivating missense gene mutations in the ligand-binding domain of the AR in tumors from two of nine nonresponders positive with the NH 2 -terminal AR antisera but negative for COOH-terminal immunoreactivity and lacking specific, high-affinity dihydrotestosterone binding in tumor cytosol fractions. Tumors with more AR than the median level (37 fmol/mg protein) had significantly lower levels of PR (30 fmol/mg protein) than tumors with low AR (PR; 127 fmol/mg protein) despite comparable levels of ER. Ligand-dependent activation of the AR in human T47D and MCF-7 breast cancer cells resulted in inhibition of estradiol-stimulated cell proliferation and a reduction in the capacity of the ER to induce expression of the PR. These effects could be reversed using a specific AR antisense oligonucleotide. Increasing the ratio of AR to ER resulted in a greater androgen-dependent inhibition of ER function. Collectively, these data suggest that reduced levels of AR or impaired AR function contribute to the failure of MPA therapy potentially due to abrogation of the inhibitory effect of AR on ER signaling. (Cancer Res 2005; 65(18): 8487-96)

Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer

“…5,9) and previous studies have indicated the potential for AR to predict disease progression (10,11). In addition, we have reported that the level of the AR predicts both the likelihood and the duration of response to therapy with the synthetic progestin, medroxyprogesterone acetate (12), and that disease progression after medroxyprogesterone acetate therapy is associated with inactivating mutations in the AR gene (13). What is unclear, however, is the mechanism by which androgens influence hormonal sensitivity and disease progression in breast cancer and how best to use AR signaling to modulate the growth of breast cancer cells (9,14).…”

Control of Androgen Receptor Signaling in Prostate Cancer by the Cochaperone Small Glutamine–Rich Tetratricopeptide Repeat Containing Protein α

“…To investigate the role of aSGT in AR function in vivo, we undertook quantitative immunohistochemistry of these two proteins in a cohort of human prostate epithelium (Fig. 4A) using previously described methods (14). A correlation between AR and aSGT immunoreactivity was observed in primary tumors (R = 0.469, P = 0.009; Fig.…”

“…Immunoblot analysis was done using rabbit AR U407 (1:1,000), N20 (1:1,000; Santa Cruz Biotechnology), or C-19 (1:1,000; Santa Cruz Biotechnology), rabbit aSGT (1:3,000; Zymed Laboratories, Inc.), and/or goat h-actin (I19; Santa Cruz Biotechnology) antisera (14). For immunoprecipitation, lysates of COS-1 cells (untransfected or transfected with control, AR, and/or aSGT expression vectors) were incubated with 5 Ag of the appropriate antisera.…”

Androgen receptors as a prognostic and predictive factor in breast cancer.

“…The role of androgens and their receptor in the progression of breast cancer remains unexplained [22][23][24][25]. Many studies showed that elevated level of androgens is directly proportional to the risk of developing breast cancer in postmenopausal women [26][27][28][29][30].…”