Activation of beta-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation.
The Wnt/beta-catenin signaling pathway is critical for normal mammalian development, the specification of epidermal cells and neoplastic transformation of intestinal epithelium. However, precise molecular information regarding cell-specific responses to beta-catenin signaling has been limited. This question was addressed using a mouse model in which exon 3 of the beta-catenin gene was deleted in several cell types with loxP-mediated recombination utilizing a Cre transgene under control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). The stabilization of beta-catenin in prostate epithelium resulted in hyperplasias and extensive transdifferentiation into epidermal-like structures, which expressed keratins 1 and 6, filaggrin, loricrin and involucrin. The cell-specific loss of NKCC1 protein and reduced nuclear Stat5a is further suggestive of a loss of prostate epithelial characteristics. In addition to the prostate, hyperplasias and squamous metaplasias were detected in epithelia of the epididymis, vas deferens, coagulating gland, preputial gland and salivary gland. However, and in contrast to a recent study, no lesions reminiscent of high-grade prostate intraepithelial neoplasia were detected. Since beta-catenin was activated in several cell types and impinged upon the viability of these mice, it was not possible to evaluate the cumulative effect over more than 3 months. To assess long-term consequences of beta-catenin activation, mutant and control prostate tissues were transplanted into the mammary fat pads of wild-type males. Notably, squamous metaplasias, intra-acinous hyperplasia and possible neoplastic transformation were observed after a total of 18 weeks of beta-catenin stimulation. This suggests that the transdifferentiation into squamous metaplasias is an early response of endoderm-derived cells to beta-catenin, and that the development of intra-acinous hyperplasias or neoplastic foci is a later event.
Bierie
Brian
B
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Nozawa
Masahiro
M
Renou
Jean-Pierre
JP
Shillingford
Jonathan M
JM
Morgan
Fanta
F
Oka
Takami
T
Taketo
Makoto M
MM
Cardiff
Robert D
RD
Miyoshi
Keiko
K
Wagner
Kay-Uwe
KU
Robinson
Gertraud W
GW
Hennighausen
Lothar
L
D000273:Adipose Tissue; D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D015415:Biomarkers; D002454:Cell Differentiation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004707:Endoderm / Q000166:cytology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006965:Hyperplasia; D008297:Male; D008321:Mammary Glands, Animal; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D011467:Prostate / Q000473:pathology* / Q000637:transplantation; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D020079:Terminal Repeat Sequences; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D019076:Transgenes; D016042:Transplantation, Heterotopic; D051176:beta Catenin
D000943:Antigens, Differentiation; D015415:Biomarkers; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051176:beta Catenin