Abstract
Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer.
Highlights
Elucidating the cell type(s) of origin of cancer and the molecular drivers of tumor initiation is of fundamental importance in understanding the basis of distinct tumor subtypes as well as differences in treatment response and patient outcomes (Blanpain, 2013; Rycaj and Tang, 2015; Shibata and Shen, 2013; Visvader, 2011)
We found that the percentage of lineage-marked YFP-positive cells, corresponding to CARNs, was not significantly different (p=0.51) between the control (0.36 ± 0.17%, n = 5 mice) and Androgen receptor (AR)-deleted mice (0.31 ± 0.06%, n = 5 mice) (Figure 1B,C)
These YFP-positive cells expressed the luminal markers cytokeratins 8 and 18 (CK8 and Cytokeratin 18 (CK18)), but not cytokeratin 5 (CK5) and p63, indicating that AR deletion does not alter the luminal phenotype of CARNs (Figure 1D)
Summary
Elucidating the cell type(s) of origin of cancer and the molecular drivers of tumor initiation is of fundamental importance in understanding the basis of distinct tumor subtypes as well as differences in treatment response and patient outcomes (Blanpain, 2013; Rycaj and Tang, 2015; Shibata and Shen, 2013; Visvader, 2011). In the case of the prostate, both the specific identity of stem/progenitor cells as. Cancer Biology Developmental Biology and Stem Cells eLife digest Most prostate tumors rely on male hormones – called androgens – to survive. Aggressive prostate cancer is often treated with drugs that block androgens, which usually cause the prostate tumors to shrink. One class of the drugs works by binding to and inactivating the androgen receptor protein on prostate cancer cells. Aggressive prostate tumors can often become resistant to these anti-androgen therapies
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