Menin has also been found to be predominantly present at TSS ( Agarwal et al., 2007 Cheng et al., 2014 Scacheri et al., 2006). H3K4me3 is an epigenetic mark of active transcription and is localized primarily to transcription start sites (TSS) ( Santos-Rosa et al., 2002). Aberrant H3K4me3 is considered to contribute to MEN1 tumorigenesis as simultaneous knock out of the H3K4me3 demethylase Rbp2/Kdm5a resulted in longer survival in a MEN1 mouse model in which mice develop insulinomas ( Lin et al., 2011). Menin was found to be an integral part of mixed-lineage leukemia MLL1/MLL2 (lysine methyltransferase ) containing protein complexes that have methyltransferase activity directed at trimethylation of lysine 4 of Histone H3 (H3K4me3) ( Huang et al., 2012 Hughes et al., 2004 Yokoyama et al., 2004). Most of the interacting proteins indicate a role for menin in transcriptional regulation, either as a co-activator or a co-repressor ( Matkar et al., 2013). Over the years, many menin-interacting proteins have been reported. Menin is a ubiquitously expressed nuclear protein that has no intrinsic enzymatic activity. A similar proliferative function of menin has recently been shown in sporadic androgen receptor (AR) expressing prostate cancer ( Malik et al., 2015).
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Menin is able to interact with and co-activate the estrogen receptor alpha (ERα), a critical driver in approximately 70% of sporadic breast cancer cases ( Dreijerink et al., 2006 Imachi et al., 2010). MEN1 gene mutations are uncommon and expression of the MEN1 gene product menin has been reported to be involved in resistance to endocrine therapy ( Imachi et al., 2010 TCGA, 2012). In contrast, in sporadic breast cancers the MEN1 gene appears to exert a proliferative function. Moreover, genetic loss of function MEN1 mouse models show increased incidence of both in situ and invasive mammary cancer ( Seigne et al., 2013). Consistent with this, breast tumors in MEN1 patients show complete loss of the MEN1 gene ( Dreijerink et al., 2014). Female MEN1 patients are at increased risk for developing breast cancer suggesting a tumor suppressive role. Previous studies have suggested however that the MEN1 gene has a dual role in breast tumorigenesis. Multiple endocrine neoplasia type 1 (MEN1) is caused by inactivating germline mutations of the MEN1 gene and is predominantly characterized by parathyroid adenomas, pituitary adenomas and pancreatic and duodenal neuroendocrine tumors ( Chandrasekharappa et al., 1997 Thakker et al., 2012).
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