We have described a rare group of prostate adenocarcinomas that show aberrant expression of p63, a protein strongly expressed in prostatic basal cells and absent from usual-type acinar prostate cancers. The partial basal-like immunophenotype of these tumors is intriguing in light of the persistent debate surrounding the cell-of-origin for prostate cancer; however, their molecular phenotype is unknown. We collected 37 of these tumors on radical prostatectomy and biopsy and assessed subsets for a diverse panel of molecular markers. The majority of p63-expressing tumors were positive for the ΔNp63 isoform (6/7) by immunofluorescence and p63 mRNA (7/8) by chromogenic in situ hybridization. Despite p63 positivity, these tumors uniformly expressed luminal-type cytokeratin proteins such as CK18 (13/13), CK8 (8/8), and markers of androgen axis signaling commonly seen in luminal cells, including androgen receptor (10/11), NKX3.1 (8/8), and prostein (12/13). Conversely, basal cytokeratins such as CK14 and CK15 were negative in all cases (0/8) and CK5/6 was weakly and focally positive in 36% (4/11) of cases. Pluripotency markers including β-catenin, Oct4, and c-kit were negative in p63-expressing tumors (0/11). Despite nearly universal expression of androgen receptor and downstream androgen signaling targets, p63-expressing tumors lacked ERG rearrangements by fluorescence in situ hybridization (0/14) and ERG protein expression (0/37). No tumors expressed SPINK1 or showed PTEN protein loss (0/19). Surprisingly, 74% (14/19) of p63-expressing tumors expressed GSTP1 protein at least focally, and 33% (2/6) entirely lacked GSTP1 CpG island hypermethylation by bisulfite sequencing. In contrast to usual prostatic adenocarcinomas, prostate tumors with p63 expression show a mixed luminal/basal immunophenotype, uniformly lack ERG gene rearrangement, and frequently express GSTP1. These data strongly suggest that p63-expressing prostate tumors represent a molecularly distinct subclass and further study of this rare tumor type may yield important insights into the role of p63 in prostatic biology and the prostate cancer cell-of-origin.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $52.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Osunkoya AO, Hansel DE, Sun X et al. Aberrant diffuse expression of p63 in adenocarcinoma of the prostate on needle biopsy and radical prostatectomy: Report of 21 cases. Am J Surg Pathol 2008;32:461–467.
Giannico GA, Ross HM, Lotan T et al. Aberrant expression of p63 in adenocarcinoma of the prostate: A radical prostatectomy study. Am J Surg Pathol 2013;37:1401–1406.
Ali TZ, Epstein JI . Basal cell carcinoma of the prostate: A clinicopathologic study of 29 cases. Am J Surg Pathol 2007;31:697–705.
Toubaji A, Albadine R, Meeker AK et al. Increased gene copy number of ERG on chromosome 21 but not TMPRSS2-ERG fusion predicts outcome in prostatic adenocarcinomas. Mod Pathol 2011;24:1511–1520.
Lotan TL, Gurel B, Sutcliffe S et al. PTEN protein loss by immunostaining: Analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011;17:6563–6573.
Suh EK, Yang A, Kettenbach A et al. P63 protects the female germ line during meiotic arrest. Nature 2006;444:624–628.
Wang F, Flanagan J, Su N et al. RNAscope: A novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn 2012;14:22–29.
Yegnasubramanian S, Lin X, Haffner MC et al. Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes (COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation. Nucleic Acids Res 2006;34:e19.
Parsons JK, Saria EA, Nakayama M et al. Comprehensive mutational analysis and mRNA isoform quantification of TP63 in normal and neoplastic human prostate cells. Prostate 2009;69:559–569.
Uchida K, Ross H, Epstein J et al. DeltaNp63 isoforms of p63 in aberrant diffuse p63 positive prostate cancer. Mod Path 2012;25:247.
Romano RA, Ortt K, Birkaya B et al. An active role of the DeltaN isoform of p63 in regulating basal keratin genes K5 and K14 and directing epidermal cell fate. PLoS One 2009;4:e5623.
Harper ME, Glynne-Jones E, Goddard L et al. Expression of androgen receptor and growth factors in premalignant lesions of the prostate. J Pathol 1998;186:169–177.
Haffner MC, Aryee MJ, Toubaji A et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 2010;42:668–675.
Rubin MA, Maher CA, Chinnaiyan AM . Common gene rearrangements in prostate cancer. J Clin Oncol 2011;29:3659–3668.
Tomlins SA, Rhodes DR, Yu J et al. The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell 2008;13:519–528.
Carver BS, Tran J, Gopalan A et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 2009;41:619–624.
King JC, Xu J, Wongvipat J et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet 2009;41:524–526.
Han B, Mehra R, Lonigro RJ et al. Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression. Mod Pathol 2009;22:1083–1093.
Bismar TA, Yoshimoto M, Vollmer RT et al. PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer. BJU Int 2011;107:477–485.
Lee WH, Morton RA, Epstein JI et al. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci USA 1994;91:11733–11737.
Yegnasubramanian S, Kowalski J, Gonzalgo ML et al. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res 2004;64:1975–1986.
Pignon JC, Grisanzio C, Geng Y et al. P63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia. Proc Natl Acad Sci USA 2013;110:8105–8110.
Pettersson A, Graff RE, Bauer SR et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: A cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012;21:1497–1509.
Mills AA, Zheng B, Wang XJ et al. P63 is a P53 homologue required for limb and epidermal morphogenesis. Nature 1999;398:708–713.
Yang A, Schweitzer R, Sun D et al. P63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999;398:714–718.
Signoretti S, Waltregny D, Dilks J et al. P63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000;157:1769–1775.
Signoretti S, Pires MM, Lindauer M et al. P63 regulates commitment to the prostate cell lineage. Proc Natl Acad Sci USA 2005;102:11355–11360.
Romano RA, Smalley K, Magraw C et al. DeltaNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development 2012;139:772–782.
Choi N, Zhang B, Zhang L et al. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 2012;21:253–265.
Wang ZA, Mitrofanova A, Bergren SK et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol 2013;15:274–283.
Grisanzio C, Signoretti S . P63 in prostate biology and pathology. J Cell Biochem 2008;103:1354–1368.
Yi R, Poy MN, Stoffel M et al. A skin microRNA promotes differentiation by repressing 'stemness'. Nature 2008;452:225–229.
Lawson DA, Zong Y, Memarzadeh S et al. Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc Natl Acad Sci USA 2010;107:2610–2615.
Goldstein AS, Huang J, Guo C et al. Identification of a cell of origin for human prostate cancer. Science 2010;329:568–571.
Stoyanova T, Cooper AR, Drake JM et al. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proc Natl Acad Sci USA 2013;110:20111–20116.
Lu TL, Huang YF, You LR et al. Conditionally ablated pten in prostate basal cells promotes basal-to-luminal differentiation and causes invasive prostate cancer in mice. Am J Pathol 2013;182:975–991.
Nakayama M, Bennett CJ, Hicks JL et al. Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: A detailed study using laser-capture microdissection. Am J Pathol 2003;163:923–933.
Mosquera JM, Perner S, Genega EM et al. Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 2008;14:3380–3385.
Funding for this research was provided in part by a Prostate Cancer Foundation Young Investigator Award (TLL), a David H. Koch Research Award (TLL), and the NIH/NCI Prostate SPORE P50CA58236.
The authors declare no conflict of interest.
About this article
Morphological and Immunohistochemical Biomarkers in Distinguishing Prostate Carcinoma and Urothelial Carcinoma: A Comprehensive Review
International Journal of Surgical Pathology (2019)
Immunohistochemical panel to characterize canine prostate carcinomas according to aberrant p63 expression
PLOS ONE (2018)
ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63
The Prostate (2018)
Cold Spring Harbor Perspectives in Medicine (2018)