Abstract
BackgroundMutations 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.MethodsTo 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.ResultsSix 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.ConclusionOur work suggests the possible involvement of Men1 inactivation in the tumorigenesis of the prostate gland.
Highlights
Mutations of the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome
A proportion of aged heterozygous Men1 mutant mice develop prostate cancer To determine the effect of Men1 inactivation on prostate cancer development in mice, we followed a cohort of 47 male mutant mice (Men1+/-) and 23 wild-type (Men1+/+) age-matched littermate mice from 18 to 26 months of age, based on a previous study that showed no prostate cancer in younger mice [6]
One prostate cancer case was previously documented in an independent heterozygous Men1 mutant mouse cohort [7], to our knowledge, the present study is the first systematic evaluation and characterisation of prostate cancer related to the inactivation of the Men1 gene
Summary
Mutations of the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome. We have found three cases (3/36, 8,3%) of breast cancer in heterozygous Men female mice [6], and Crabtree et al documented one case of prostate cancer developed in their heterozygous Men mouse cohort [7] Consistent with these observations, Dreijerink et al have shown that menin interacts physically, in a ligand-dependent manner, with several nuclear receptors, such as the oestrogen receptor (ER) [9] and peroxisome proliferator activated receptor gamma (PPARg) [10], and that menin acts as a coactivator of nuclear receptor mediated transcription. Gene expression analyses further revealed that the expression of CDKN1B (cyclin-dependent kinase inhibitor 1B, called p27), a known menin target gene [11,12], was markedly reduced in the analysed prostatic carcinomas
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