Fellowship for Stevens: Erbin-mediated regulation of colon cancer progression

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 142,000 new cases and 51,000 deaths are predicted for the year 2013; this mortality is predominantly due to metastasis to other organs. If advances are to be made in the survival of colorectal cancer patients, a better understanding of the molecular mechanisms involved in CRC metastasis is required. In this proposed study, I plan to investigate the role of Erbin, a basolateral-localized scaffolding protein, in inhibiting CRC invasion and metastasis. This proposal centers on a novel discovery that Erbin plays an important role in suppressing epithelial-mesenchymal transition (EMT) of CRC cells by controlling cell polarity. The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Increasing evidence has suggested that disruption of this cellular polarity promotes the malignant progression of cancer cells. However, the molecular mechanism underlying polarity regulation in the initiation and progression of CRC remains largely unknown. In my preliminary experiments, I have found that knockdown of Erbin induces an EMT-like phenotype and promotes migration in CRC cells. In addition, silencing Erbin resulted in the disruption of cell polarity in 3D cultures, mislocalization of EGF receptors (EGFRs), and an increase in the activation of EGFR signaling. To begin to elucidate the underlying molecular mechanism, we identified PHLPP, a novel tumor suppressor in CRC, as an interacting protein of Erbin. Interestingly, loss of Erbin expression resulted in an increase in both Akt and ERK activation similar to that observed in PHLPP knockdown cells. I hypothesize that Erbin serves as a scaffolding protein, bringing PHLPP in close proximity with its substrates. This interaction between PHLPP and Erbin could provide the spatial-temporal control necessary to suppress oncogenic Akt and RAS/RAF signaling. Furthermore, the analysis of Erbin mRNA expression in two large sets of CRC patient samples revealed that Erbin is significantly downregulated in cancer specimens compared to normal controls, thus supporting the role of Erbin as a tumor suppressor in CRC. In light of our preliminary findings, the central hypothesis driving this proposal is that Erbin plays a critical role in inhibiting CRC metastasis and it functions by maintaining cell polarity to inhibit Akt- and RAS/RAF-mediated oncogenic signaling. The following specific aims are proposed: 1) to define the functional effects of Erbin in maintaining cell polarity and inhibiting CRC migration and invasion. We will elucidate the molecular mechanism by which loss of Erbin promotes CRC metastasis in vivo and to evaluate Erbin as a potential prognostic marker in CRC; 2) to determine the role of Erbin in regulating PHLPP-dependent inhibition of Akt and RAS/RAF pathways. Defining the role of Erbin in tumor metastasis and response to chemotherapy will have sustained impact on improving CRC patient care.