Activation of β-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation

被引:108
作者
Bierie, B
Nozawa, M
Renou, JP
Shillingford, JM
Morgan, F
Oka, T
Taketo, MM
Cardiff, RD
Miyoshi, K
Wagner, KU
Robinson, GW
Hennighausen, L
机构
[1] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA
[2] INRA, Jouy En Josas, France
[3] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto 6068501, Japan
[4] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA
[5] Univ Tokushima, Dept Biochem, Sch Dent, Tokushima 7708504, Japan
[6] Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Nebraska Med Ctr, Omaha, NE USA
关键词
beta-catenin; cell identity; transdifferentiation; neoplasia; prostate;
D O I
10.1038/sj.onc.1206426
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3875 / 3887
页数:13
相关论文
共 54 条
[31]   Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin [J].
Merrill, BJ ;
Gat, U ;
DasGupta, R ;
Fuchs, E .
GENES & DEVELOPMENT, 2001, 15 (13) :1688-1705
[32]   Activation of different Wnt/β-catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors [J].
Miyoshi, K ;
Rosner, A ;
Nozawa, M ;
Byrd, C ;
Morgan, F ;
Landesman-Bollag, E ;
Xu, X ;
Seldin, DC ;
Schmidt, EV ;
Taketo, MM ;
Robinson, GW ;
Cardiff, RD ;
Hennighausen, L .
ONCOGENE, 2002, 21 (36) :5548-5556
[33]   Mammary epithelial cells are not able to undergo pregnancy-dependent differentiation in the absence of the helix-loop-helix inhibitor Id2 [J].
Miyoshi, K ;
Meyer, B ;
Gruss, P ;
Cui, YZ ;
Renou, JP ;
Morgan, FV ;
Smith, GH ;
Reichenstein, M ;
Shani, M ;
Hennighausen, L ;
Robinson, GW .
MOLECULAR ENDOCRINOLOGY, 2002, 16 (12) :2892-2901
[34]   Activation of β-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias [J].
Miyoshi, K ;
Shillingford, JM ;
Le Provost, F ;
Gounari, F ;
Bronson, R ;
von Boehmer, H ;
Taketo, MM ;
Cardiff, RD ;
Hennighausen, L ;
Khazaie, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (01) :219-224
[35]   Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium [J].
Miyoshi, K ;
Shillingford, JM ;
Smith, GH ;
Grimm, SL ;
Wagner, KU ;
Oka, T ;
Rosen, JM ;
Robinson, GW ;
Hennighausen, L .
JOURNAL OF CELL BIOLOGY, 2001, 155 (04) :531-542
[36]   Epithelial defect in prostates of Stat5a-null mice [J].
Nevalainen, MT ;
Ahonen, TJ ;
Yamashita, H ;
Chandrashekar, V ;
Bartke, A ;
Grimley, PM ;
Robinson, GW ;
Hennighausen, L ;
Rui, H .
LABORATORY INVESTIGATION, 2000, 80 (07) :993-1006
[37]  
Niemann C, 2002, DEVELOPMENT, V129, P95
[38]   Characterization of ESE-2, a novel ESE-1-related Ets transcription factor that is restricted to glandular epithelium and differentiated keratinocytes [J].
Oettgen, P ;
Kas, K ;
Dube, A ;
Gu, XS ;
Grall, F ;
Thamrongsak, U ;
Akbarali, Y ;
Finger, E ;
Boltax, J ;
Endress, G ;
Munger, K ;
Kunsch, C ;
Libermann, TA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (41) :29439-29452
[39]  
Polakis P, 2000, GENE DEV, V14, P1837
[40]   DISTRIBUTION OF LACTOFERRIN IN THE NORMAL AND INFLAMED HUMAN PROSTATE - AN IMMUNOHISTOCHEMICAL STUDY [J].
REESE, JH ;
MCNEAL, JE ;
GOLDENBERG, SL ;
REDWINE, EA ;
SELLERS, RG .
PROSTATE, 1992, 20 (01) :73-85