title: Human α(2)β(1)(HI) CD133(+VE) epithelial prostate stem cells express low levels of active androgen receptor.
abstract: Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Williamson
authors.forename: Anastasia C
authors.initials: AC
authors.lastname: Hepburn
authors.forename: Laura
authors.initials: L
authors.lastname: Wilson
authors.forename: Kelly
authors.initials: K
authors.lastname: Coffey
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Ryan-Munden
authors.forename: Deepali
authors.initials: D
authors.lastname: Pal
authors.forename: Hing Y
authors.initials: HY
authors.lastname: Leung
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.forename: Rakesh
authors.initials: R
authors.lastname: Heer
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; C410798:AR protein, human; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D011944:Receptors, Androgen; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human