The general goal of our research is to identify factors that control endocrine tumorigenesis, with a focus on abnormal growth of the insulin-secreting pancreatic β-cells. Investigating the molecular and genetic mechanisms of tumorigenesis will not only provide insights into the pathways of tumor syndromes, but it could also define novel pathways and processes involved in normal cell growth regulation.
We study the molecular and genetic basis of endocrine tumorigenesis, particularly endocrine pancreatic neoplasms of the islet β-cells, to understand how gene regulatory events contribute to endocrine cell transformation.
Endocrine tumors develop due to abnormal cell proliferation and function of hormone-producing cells. These tumors can occur sporadically or within familial tumor syndromes such as multiple endocrine neoplasia type 1 (MEN1), a disease characterized by germline-inactivating mutations in the MEN1 tumor-suppressor gene that encodes menin. These mutations predispose to tumors of the parathyroids, anterior pituitary, and enteropancreatic neuroendocrine tissues. Also, somatic inactivation of one or both copies of the MEN1 gene is observed in 20 to 30 percent of sporadic (non-hereditary) parathyroid tumors, and in 30 to 40 percent of sporadic pancreatic neuroendocrine tumors. Studies in mouse models have demonstrated that Men1 homozygous-null mice are embryonic-lethal, and heterozygous mice show tumors similar to those found in the human MEN1 syndrome. However, how menin loss initiates tumors in specific endocrine organs is not completely understood. Thus, it is important to study tumor pathogenesis from menin loss.
Menin is a 610-amino acid nuclear protein that interacts with a variety of factors involved in transcriptional regulation, such as transcription factors and histone-modifying protein complexes. However, how the loss of menin in these interactions affects growth-related processes of specific endocrine cells has not been clearly determined. We propose that studying menin-regulated processes will help uncover the factors responsible for tumors that arise even without MEN1 gene mutation. Therefore, we are using menin as a model to identify regulatory factors that operate downstream of menin and that could be independently responsible for initiating endocrine tumorigenesis.
The genetics and pathogenesis of sporadic endocrine tumors, particularly tumors of the pituitary, parathyroid, and pancreatic neuroendocrine tissues without MEN1 gene inactivation, require further study. Researchers also need to examine whether processes perturbed upon MEN1 gene loss could point to novel mechanisms of tumorigenesis and how menin loss initiates tumors in specific endocrine organs.