Transcriptional gene regulation in eukaryotic cells

The research in our laboratory involves defining the molecular mechanisms that regulate gene expression in pancreatic and mammary gland epithelial cells during development and in cases of tumor initiation and progression. We have focused on the basic helix-loop-helix (bHLH) transcription factor family since these proteins are essential to controlling both developmental and cell proliferation events. Alterations in bHLH factor activity, or in bHLH gene expression patterns, often correlate with the development of pancreatic and breast cell tumors.

Pancreas development

We have identified a novel bHLH factor, Mist1, that is expressed in developing and adult pancreatic tissues. Mist1 gene expression is restricted to the exocrine gland portion of the pancreas, which is the area from which most pancreatic tumors are derived. It is this adult expression pattern of Mist1 that we are particularly interested in since the Mist1 gene maps to a region of mouse chromosome 5 that has been implicated in several pancreatic tumors. In order to understand the role of Mist1 in the development and function of these cell types we have generated a Mist1 null (Mist1^KO) mouse in which the Mist1 gene has been deleted. Interestingly, the secretory cells of Mist1^KO mice exhibit a highly disorganized acinar structure. Functional studies, coupled with gene array analysis, has revealed that Mist1^KO mice no longer express the gap junction protein connexin 32. The loss of connexin 32 expression leads to cells that fail to communicate. Future studies are aimed at identifying additional Mist1 target genes in the hope of understanding how this key transcription factor functions during development.

Pancreatic cancer mouse models

One of the goals of our laboratory is to generate transgenic mouse tumor models. We plan to use these models to study a variety of cancers so that new therapeutic strategies can be developed that will inhibit tumor formation and metastasis. We recently generated (in collaboration with Drs. David Tuveson and Tyler Jacks) a novel pancreatic cancer animal model. Our strategy was to introduce a mutated K-Ras oncogene (K-RasG12D) into the Mist1 locus so that the activated K-Ras gene is expressed in the exocrine pancreas. As expected, these mice develop a variety of pancreatic cancers that often metastasize. Interestingly, the pancreatic tumor phenotype becomes much more pronounced when the Mist1-K-Ras mice are crossed to the Mist1^KO mice. These results suggest that Mist1 plays a role as a potential tumor suppressor gene in normal pancreas homeostasis. Future studies will focus on understanding how Mist1 alters the K-Ras signaling pathways that are constitutively active in these animals.

Mammary gland development and breast cancer

Our laboratory is also interested in understanding the molecular and genetic events that control cellular specificity, differentiation and growth control of mammary epithelial cells. The mammary gland is unique because it undergoes a continuous developmental program in the adult organism that covers the stages of virgin, pregnancy, lactation and involution. We have shown that the bHLH factor Mist1 is expressed exclusively in quiescent mammary gland cells and not in breast tumor cells. Interestingly, forced expression of Mist1 in tumor cells results in a cessation of cellular proliferation, suggesting that the absence of Mist1 in metastatic tumors may permit their uncontrolled growth. Our working hypothesis is that loss of Mist1 expression in human tumor cells releases them from the normal growth control associated with the bHLH transcriptional circuitry. We are continuing to test this model and are generating new Mist1-Cre mouse lines that will be used to activate specific breast tumor promotion genes in a variety of transgenic mouse cancer model systems.