Breast cancer stem cells (BCSC) have been implicated in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. The origins of BCSCs remain controversial due to tumor heterogeneity and the presence of such small side populations for study, but nonetheless, cell surface markers and their correlation with BCSC functionality continue to be identified. BCSCs are driven by persistent activation of developmental pathways, such as Notch, Wnt, Hippo, and Hedgehog and new treatment strategies that are aimed at these pathways are in preclinical and clinical development.

Carcinoids and neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the neuroendocrine cells of the GI tract, endocrine pancreas and the respiratory system. NETs remain significantly understudied with respect to molecular mechanisms of pathogenesis, particularly the role of cell fate signaling systems like Notch. The abundance of literature on the Notch pathway is a testament to its complexity in different cellular environments. Notch receptors can function as oncogenes in some contexts, and tumor suppressors in others. The genetic heterogeneity of NETs suggests that to fully understand the roles and the potential therapeutic implications of Notch signaling in NETs, a comprehensive analysis of Notch expression patterns and potential roles across all NET subtypes is required.

Menin, the product of the MEN1 gene, functions as a tumor suppressor and was first identified in 1997 due to its causative role in the endocrine tumor disorder multiple endocrine neoplasia, type 1 (MEN1). More recently, menin has been identified as a key player in pancreatic islet biology with the observation of an inverse relationship between menin levels and pancreatic islet proliferation. However, the factors regulating menin and the MEN1 gene in the pancreas are poorly understood. Here, we describe the regulation of menin by miR-24 and demonstrate that miR-24 directly decreases menin levels and impacts downstream cell cycle inhibitors in MIN6 insulinoma cells and in βlox5 immortalized β-cells. This regulation of menin impacts cell viability and proliferation in βlox5 cells. Furthermore, our data show a feedback regulation between miR-24 and menin that is present in the pancreas, suggesting that miR-24 regulates menin levels in the pancreatic islet.

Gastroenteropancreatic neuroendocrine neoplasms are a rare, diverse group of neuroendocrine tumors that form in the pancreatic and gastrointestinal tract, and often present with side effects due to hormone hypersecretion. The pathogenesis of these tumors is known to be linked to several genetic disorders, but sporadic tumors occur due to dysregulation of additional genes that regulate proliferation and metastasis, but also the epigenome. Epigenetic regulation in these tumors includes DNA methylation, chromatin remodeling and regulation by noncoding RNAs. Several large studies demonstrate the identification of epigenetic signatures that may serve as biomarkers, and others identify innovative, epigenetics-based targets that utilize both pharmacological and theranostic approaches towards the development of new treatment approaches.

Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines βlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs.