Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice.
BACKGROUND
Mutations of the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome. Our group and others have shown that Men1 disruption in mice recapitulates MEN1 pathology. Intriguingly, rare lesions in hormone-dependent tissues, such as prostate and mammary glands, were also observed in the Men1 mutant mice.


METHODS
To study the occurrence of prostate lesions, we followed a male mouse cohort of 47 Men1+/- mice and 23 age-matched control littermates, starting at 18 months of age, and analysed the prostate glands from the cohort.


RESULTS
Six Men1+/- mice (12.8%) developed prostate cancer, including two adenocarcinomas and four in situ carcinomas, while none of the control mice developed cancerous lesions. The expression of menin encoded by the Men1 gene was found to be drastically reduced in all carcinomas, and partial LOH of the wild-type Men1 allele was detected in three of the five analysed lesions. Using immunostaining for the androgen receptor and p63, a basal epithelial cell marker, we demonstrated that the menin-negative prostate cancer cells did not display p63 expression and that the androgen receptor was expressed but more heterogeneous in these lesions. Furthermore, our data showed that the expression of the cyclin-dependent kinase inhibitor CDKN1B (p27), a Men1 target gene known to be inactivated during prostate cell tumorigenesis, was notably decreased in the prostate cancers that developed in the mutant mice.


CONCLUSIONS
Our work suggests the possible involvement of Men1 inactivation in the tumorigenesis of the prostate gland.
Seigne
Christelle
C
CNRS UMR5201, Laboratoire de Génétique Moléculaire, Signalisation et Cancer, Centre Léon Bérard, Lyon F-69008, France.
Fontanière
Sandra
S
Carreira
Christine
C
Lu
Jieli
J
Tong
Wei-Ming
WM
Fontanière
Bernard
B
Wang
Zhao-Qi
ZQ
Zhang
Chang Xian
CX
Frappart
Lucien
L
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000375:Aging; D000818:Animals; D015139:Blotting, Southern; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006579:Heterozygote; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011944:Receptors, Androgen / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
C484898:Men1 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27