Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers

Abstract

Prostate cancer and breast cancer are the most common malignancies in the western world. Androgen receptor (AR) and PTEN both have been well documented to have important roles in prostate carcinogenesis. In contrast, AR and PTEN in breast carcinogenesis have not been well studied. Furthermore, the crosstalk and connection between those two pathways remain unclear. Increased AR expression in prostate cancers, combined with decreased PTEN expression, portends a poor clinical outcome. Paradoxically, both high AR and high PTEN levels, detected by immunohistochemistry, in primary breast carcinomas have been associated with better disease-free survival. Here, we performed in silico analysis of publicly available microarray data sets from prostate or breast carcinomas. We found an inverse correlation between AR and PTEN transcript expression in prostate cancer tissues in contrast to the positive correlation in breast cancer. These data led us to hypothesize that AR may directly affect PTEN transcriptional regulation in prostate and breast cancer cells. Here, we show for the first time that AR inhibits PTEN transcription in prostate cancer cells, whereas AR upregulates PTEN transcription in breast cancer cells, which mechanistically explains both the immunohistochemical PTEN-AR expressional data noted in clinical trials and in our in silico analysis of the transcriptomes of breast and prostate cancers. In addition, we have fine-mapped the AR-binding motif within the PTEN promoter. Here we show that, in patients with Cowden syndrome, an inherited cancer syndrome caused by germline mutations scattered throughout PTEN, point variants affecting the 3 0 end of the AR-binding motif result in abrogation of androgen-mediated transcriptional regulation of PTEN expression. We may speculate that the differential AR effect on PTEN may begin to explain organ-specific and perhaps sex-specific neoplasia predisposition in Cowden syndrome, as well as why only a fraction of women with germline PTEN mutations develop breast cancer, depending on the androgen steroid milieu and levels.

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

“…PTEN promoter (full-length, truncations and mutants) activity was measured by luciferase, and these constructs were made as defined in Ref. 22, and pRL-CMV Renilla reporter for normalization to transfection efficiency. Transient transfection was achieved using GeneFect (Alkali Scientific, Inc.).…”

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

“…Unaromatizable androgens, such as dihydrotestosterone (DHT), inhibit tumor proliferation and induce apoptosis by activating androgen receptor (AR) in AR þ /ER þ breast cancers (7)(8)(9). Among all female breast carcinomas, 60% to 70% are AR positive.…”

“…The tumor suppressor gene PTEN (deleted on chromosome 10) is one of the most frequently mutated or deleted genes in inherited and sporadic human cancers, including breast carcinomas (12). We have previously shown that AR is positively correlated with PTEN expression in breast carcinomas, which is due to the direct activation of PTEN transcription, mediated by an androgen response element (ARE) in the PTEN promoter (9,13).…”

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

“…However, P-AKT expression was increased in intraepithelial neoplastic glands, which were only present in ugePTENARKO. Therefore, in contrast to breast and prostate cancer cells (Wang et al 2011), the AR inactivation in uterine glandular cells did not appear to affect AKT signaling pathway. However, as intraepithelial neoplastic glands were only present in ugePTENARKO, further investigation (i.e., cell culture) is warranted to determine the direct role of glandular epithelial AR in AKT pathway.…”

“…Similarly, androgens may regulate ERα expression as shown by testosterone-induced suppression of ERα expression in mammary tissue (Zhou et al 2000). Alternatively, AR could interact with PTEN to indirectly modify ERα expression as seen in prostate and breast cancer cells (Wang et al 2011). Therefore, we explored whether glandular epithelial AR inactivation modified ERα expression in PTEN-deleted uterus.…”