An oncogenic role for the multiple endocrine neoplasia type 1 gene in prostate cancer

Department of Urology, University of California at San Francisco Comprehensive Cancer Center, UCSF, San Francisco, CA 94143, USA.
Prostate cancer and prostatic diseases (Impact Factor: 3.43). 10/2008; 12(2):184-91. DOI: 10.1038/pcan.2008.45
Source: PubMed


Prostate cancer is the second leading cause of cancer related deaths in US men, largely because of metastasis, which is ultimately fatal. A better understanding of metastasis biology will lead to improved prognostication and therapeutics. We previously reported 11q13.1 gain was independently predictive of recurrence after radical prostatectomy. Multiple endocrine neoplasia I (MEN1) maps to this region of copy number gain in aggressive prostate tumors and was shown to be the only gene at this locus at increased expression in prostate cancer. Here, we demonstrate an oncogenic role for MEN1 in prostate cancer using a variety of independent assays.

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    • "Gains at 11q have been associated with a higher risk of esophageal squamous cell carcinoma development; notably, 11q13.1–13.4 is one of the most gene-rich regions on 11q, showing DNA gains correlated with increased RNA expression in >80% of the genes mapped on this minimal region (37). Additionally, 11q13 gains were correlated with poor prognosis of patients with other tumors, such as prostate (38) and thyroid (39), larger tumor size in hepatocellular carcinoma (40), and were suggested as predictive markers of distant recurrence in patients with breast cancer (41). "
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    ABSTRACT: A significant proportion (up to 62%) of Oral Squamous Cell Carcinomas (OSCCs) may arise from oral potential malignant lesions (OPML), such as leukoplakia. Patient outcomes may thus be improved through detection of lesions at risk for malignant transformation, by identifying and categorizing genetic changes in sequential, progressive OPMLs. We conducted array comparative genomic hybridization (aCGH) analysis of 25 sequential, progressive OPMLs and same-site OSCCs from five patients. Recurrent DNA copy number gains were identified on 1p in 20/25 cases (80%) with minimal, high-level amplification regions on 1p35 and 1p36. Other regions of gains were frequently observed: 11q13.4 (68%), 9q34.13 (64%), 21q22.3 (60%), 6p21 and 6q25 (56%), 10q24, 19q13.2, 22q12, 5q31.2, 7p13, 10q24, and 14q22 (48%). DNA losses were observed in >20% of samples and mainly detected on 5q31.2 (35%), 16p13.2 (30%), 9q33.1 and 9q33.29 (25%), and 17q11.2, 3p26.2, 18q21.1, 4q34.1 and 8p23.2 (20%). Such Copy Number Alterations (CNAs) were mapped in all grades of dysplasia that progressed, and their corresponding OSCCs, in 70% of patients, indicating that these CNAs may be associated with disease progression. Amplified genes mapping within recurrent CNAs (KHDRBS1, PARP1, RAB1A, HBEGF, PAIP2, BTBD7) were selected for validation, by quantitative real-time PCR, in an independent set of 32 progressive leukoplakia, 32 OSSCs and 21 non-progressive leukoplakia samples. Amplification of BTBD7, KHDRBS1, PARP1 and RAB1A was exclusively detected in progressive leukoplakia and corresponding OSCC. BTBD7, KHDRBS1, PARP1 and RAB1A may be associated with OSCC progression. Protein-protein interaction networks were created to identify possible pathways associated with OSCC progression.
    Full-text · Article · Jan 2014 · Human Molecular Genetics
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    • "Intriguingly, a recent study reported that gain at the MEN1 locus was detected in a substantial proportion of human metastatic prostate cancers, and a trend toward increased menin expression in human prostate cancers and metastatic tissues was suggested by a meta-analysis of MEN1 expression data in prostate cancer [27]. Similarly, Imachi et al. reported that menin expression in breast cancers could be used as a prognostic factor of worse outcome [28]. "
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    ABSTRACT: 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. 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. 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. Our work suggests the possible involvement of Men1 inactivation in the tumorigenesis of the prostate gland.
    Full-text · Article · Jul 2010 · BMC Cancer
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    • "Prostate neuroendocrine tumors and carcinoids have been described in MEN2B, including cases of very young patients (Whelan et al. 1995, Goulet-Salmon et al. 2004). An 11q13.1 locus gain has been detected in aggressive prostate cancers; however, the significance of this finding and the possibility of any association with the MEN1 syndrome are still under investigation (Paris et al. 2009). Breast disease in MEN syndromes includes breast cancer, including a few case reports of MEN2 patients (Lima & Smith 1971, Nozawa et al. 2004) and the frequent occurrence of mammary gland carcinomas in older MEN1 mutant animals (Bertolino et al. 2003); however, a suspected association of MEN1 with breast malignancy remains unproven (Honda et al. 2004, Pal et al. 2009). "
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    ABSTRACT: In the context of multiple neuroendocrine tumor syndromes, reproductive abnormalities may occur via a number of different mechanisms, such as hyperprolactinemia, increased GH/IGF-1 levels, hypogonadotropic hypogonadism, hypercortisolism, hyperandrogenism, hyperthyroidism, gonadotropin hypersecretion, as well as, tumorigenesis or functional disturbances in gonads or other reproductive organs. Precocious puberty and/or male feminization is a feature of McCune-Albright syndrome (MAS), neurofibromatosis type 1 (NF1), Carney complex (CNC), and Peutz-Jeghers syndrome (PJS), while sperm maturation and ovulation defects have been described in MAS and CNC. Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare, certain lesions are characteristic and very unusual in the general population. Awareness leading to their recognition is important especially when other endocrine abnormalities coexist, as occasionally they may even be the first manifestation of a syndrome. Lesions such as certain types of ovarian cysts (MAS, CNC), pseudogynecomastia due to neurofibromas of the nipple-areola area (NF1), breast disease (CNC and Cowden disease (CD)), cysts and 'hypernephroid' tumors of the epididymis or bilateral papillary cystadenomas (mesosalpinx cysts) and endometrioid cystadenomas of the broad ligament (von Hippel-Lindau disease), testicular Sertoli calcifying tumors (CNC, PJS) monolateral or bilateral macroochidism and microlithiasis (MAS) may offer diagnostic clues. In addition, multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC, breast and endometrial cancer in CD, breast malignancies in NF1, and malignant sex-cord stromal tumors in PJS.
    Full-text · Article · Oct 2009 · Endocrine Related Cancer
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