Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia.
The present study documents that stabilization of beta-catenin is sufficient to induce lesions reminiscent of prostate intraepithelial neoplasia (PIN). Such lesions were present in all compound mutant mice and all prostate acini expressing stabilized beta-catenin. High grade PIN-like lesions resembling early human prostate cancer were detected as early as 10 weeks of age. Surprisingly, stabilization of beta-catenin in other secretory epithelia including salivary, preputial, harderian, and mammary glands induced extensive squamous metaplasia and keratinization associated with terminal differentiation of the target cells, but failed to cause neoplastic transformation. Epidermal hyperplasia, hair follicle cysts, and odontomas were also observed. The prostatic lesions exhibited upregulation of c-myc, increased rate of cellular proliferation, loss of the Na-K-Cl co-transporter NKCC1, and expression of androgen receptor. Basal cell markers such as p63 and keratin 5 were not expressed by the masses of PIN-like lesions, but were present in small foci of proliferating beta-catenin expressing basal cells. Our observations indicate that beta-catenin stabilization is a crucial event for the initiation of PIN-like lesions, but induces squamous metaplasia rather than tumorigenesis in secretory epithelia other than the prostate.
Gounari
Fotini
F
Department of Cancer Immunology and Aids, Dana Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
Signoretti
Sabina
S
Bronson
Roderick
R
Klein
Ludger
L
Sellers
William R
WR
Kum
Jennifer
J
Siermann
Anja
A
Taketo
Makoto M
MM
von Boehmer
Harald
H
Khazaie
Khashayarsha
K
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D011944:Receptors, Androgen; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D015534:Trans-Activators; D051176:beta Catenin