Abstract
The conversion of androgen receptor (AR) signaling as a mechanism of growth suppression of normal prostate epithelial cells to that of growth stimulation in prostate cancer cells is often associated with AR mutation, amplification and over-expression. Thus, down-regulation of AR signaling is commonly therapeutic for prostate cancer. The E006AA cell line was established from a hormone naïve, localized prostate cancer. E006AA cells are genetically aneuploid and grow equally well when xenografted into either intact or castrated male NOG but not nude mice. These cells exhibit: 1) X chromosome duplication and AR gene amplification, although paradoxically not coupled with increased AR expression, and 2) somatic, dominant-negative Serine-599-Glycine loss-of-function mutation within the dimerization surface of the DNA binding domain of the AR gene. No effect on the growth of E006AA cells is observed using targeted knockdown of endogenous mutant AR, ectopic expression of wild-type AR, or treatment with androgens or anti-androgens. E006AA cells represent a prototype for a newly identified subtype of prostate cancer cells that exhibit a dominant-negative AR loss-of-function in a hormonally naïve patient. Such loss-of-function eliminates AR-mediated growth suppression normally induced by normal physiological levels of androgens, thus producing a selective growth advantage for these malignant cells in hormonally naïve patients. These data highlight that loss of AR-mediated growth suppression is an independent process, and that, without additional changes, is insufficient for acquiring oncogene addiction to AR signaling. Thus, patients with prostate cancer cells harboring such AR loss-of-function mutations will not benefit from aggressive hormone or anti-AR therapies even though they express AR protein.
Highlights
Within the last decade there has been a renewed interest in androgen receptor (AR) signaling, as it pertains to normal prostatic function, prostate carcinogenesis, and metastatic progression
Koochekpour et al reported the establishment of a new human prostate cancer cell line, E006AA, which was derived from a Gleason 6 localized prostate cancer in a hormone-naıve prostate cancer patient of African American descent [20]
The epithelial origin of the E006AA cells was confirmed by positive expression for cytokeratins 8 (CK8) and 18 (CK18), whereas the stromal origin of the S006AA cells was confirmed by the positive expression of mesenchymal markers desmin and alpha-smooth muscle actin and the absence of CK8 and CK18 [20]
Summary
Within the last decade there has been a renewed interest in androgen receptor (AR) signaling, as it pertains to normal prostatic function, prostate carcinogenesis, and metastatic progression. In the presence of physiological levels of androgen, and andromedins, ligandbound AR located in the secretory luminal epithelial cell prevents the overgrowth of the epithelial compartment by suppressing cell proliferation and promoting cellular differentiation [1,2,3,4]. The importance of this cell context-dependent AR growth-suppressive ability is documented by studies showing that conditional loss of AR expression in the epithelial compartment, but not in stromal cells, results in increased luminal epithelial cell proliferation [5,6]. When a physiological level of androgen is not maintained, such as following androgen ablation, the level of andromedins decreases to a level where they can neither stimulate proliferation nor block the activation of apoptosis in the epithelial cells, and the prostate regresses [1]
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