Role of autonomous androgen receptor signaling in prostate cancer initiation is dichotomous and depends on the oncogenic signal

Abstract

The steroid hormone signaling axis is thought to play a central role in initiation and progression of many hormonally regulated epithelial tumors. It is unclear whether all cancer-initiating signals depend on an intact hormone receptor signaling machinery. To ascertain whether cell autonomous androgen receptor (AR) is essential for initiation of prostate intraepithelial neoplasia (PIN), the response of AR-null prostate epithelia to paracrine and cell autonomous oncogenic signals was assessed in vivo by using the prostate regeneration model system. Epithelial-specific loss of AR blocked paracrine FGF10-induced PIN, whereas the add back of exogenous AR restored this response. In contrast, PIN initiated by cell-autonomous, chronicactivated AKT developed independent of epithelial AR signaling. Our findings demonstrate a selective role for AR in the initiation of PIN, dependent on the signaling pathways driving tumor formation. Insights into the role of hormone receptor signaling in the initiation of epithelial tumors may help define this axis as a target for chemoprevention of carcinomas.tissue recombination | tumor promoter | tumor suppressor P harmacologic agents targeting hormone receptor signaling are widely used in therapy of carcinomas arising from the breast (estrogen receptor; ER), prostate (androgen receptor; AR) and endometrium (ER, and progesterone receptor; PR) (reviewed in refs. 1 and 2). It is unclear whether the hormone receptor signaling axis plays a causative role in initiation of these malignancies or whether it can be bypassed by oncogenic signals. Loss of PR has a protective effect in initiation of mammary tumors caused by 7,12-dimethylbenz(a) anthracene (DMBA) in mice (3). These results suggest that initiation of breast cancer via DMBA depends on PR signaling. Conversely, estrogen receptor knockout mice developed mammary tumors similar to controls in response to Wnt-1 expression (4), suggesting that initiation of these tumors is independent of ER signaling. The benefits of androgen ablation in treating prostate cancer were demonstrated decades ago (5; reviewed in ref. 6). However, the roles of autonomous and extrinsic AR in initiation of prostate cancer remain unknown.

Influence of stromal–epithelial interactions on androgen action

“…The expression of AR in the epithelium was shown to increase with higher FGF10 activity, and overexpression in mice results in prostate cancer (Memarzadeh et al 2007). The expression of AR in the epithelium is required for stromal FGF10-induced PIN in vivo (Memarzadeh et al 2011).…”

Androgens and androgen receptor signaling in prostate tumorigenesis

“…The proliferation and the survival of a subset of dysplastic prostate epithelial cells are no longer solely dependent on stromal paracrine signals (i.e. andromedins); instead, cell-autonomous AR signaling becomes active (Gao & Isaacs 1998, Gao et al 2001, Memarzadeh et al 2011. The cell-autonomous AR signaling pathologically allows androgen/AR complexes to bind to and enhance expression of survival and proliferation genes that are normally not regulated by these complexes in either intermediate cells or luminal cells (Gao & Isaacs 1998, Gao et al 2001, Memarzadeh et al 2011.…”

“…andromedins); instead, cell-autonomous AR signaling becomes active (Gao & Isaacs 1998, Gao et al 2001, Memarzadeh et al 2011. The cell-autonomous AR signaling pathologically allows androgen/AR complexes to bind to and enhance expression of survival and proliferation genes that are normally not regulated by these complexes in either intermediate cells or luminal cells (Gao & Isaacs 1998, Gao et al 2001, Memarzadeh et al 2011. Using DNA microarray or other high-throughput approaches, several studies have comparatively analyzed the expression profile of androgen-regulated genes in model cell lines and in clinical specimens derived from prostate cancer patients at different developmental stages or with varying treatment histories (see review Jin et al (2013)).…”

Stem‐Like Epithelial Cells Are Concentrated in the Distal End of the Fallopian Tube: A Site for Injury and Serous Cancer Initiation

“…S1D). To assess the clonality of regenerated spheres, human FTE were infected either with FUCGW [20] (green color marked) or FUCRW [21] (red color marked) lentivirus mixed and plated together in vitro (Fig. 1E).…”