Discovery of Akt-Regulated Transcriptional Modules Associated With Malignant Phenotypes in Breast Cancer

Career Goals and Training: My goal is to become an independent scientist and conduct high-quality breast cancer research focused on reducing mortality in patients. The recent availability of large gene expression profiles from human tumor gives us a unique opportunity to understand differences between normal and tumor cells and identify novel therapeutic targets. The proposed project is innovative in its approach to combine computational inferences with experimental validation. My mentors are Dr. Califano, the head of Systems Biology Program, and Dr. Parsons, the head of the Breast Cancer Program at Columbia University. As a member of both labs, I will receive comprehensive training in reverse engineering gene networks, breast cancer biology, and signal transduction. By attending program meetings, postdoctoral scientists can interact with scientists and clinicians, which allows basic scientists to understand the types of research that are likely to impact cancer patients.

Background: Cancer is a disease of aberrant cell signaling. Biological processes, such as cell division and survival, are tightly controlled in living organisms. Healthy cells respond to signals instructing them to divide, migrate to a new location, or undergo cell death. The signals regulating cell fate (e.g., proliferation, migration or death) are controlled by genes and the proteins they encode. These elements do not work as solitary players, but as members of complex pathways that rely on interactions between members to transmit signals. During tumor development, signaling pathways become dysfunctional and lose their ability to control cell fate. Malfunctioning signaling pathways promote growth and survival of abnormal cells, leading to cancer. Deregulated signaling pathways also promote migration of cancer cells to new locations in the body, leading to metastasis. Analyses of tumors have revealed that the Akt signaling pathway is deregulated in 70% of breast cancer tumors. Akt is one of the critical signaling hubs in the cell that regulates several functions such as proliferation, cell death, and metastasis. An increased level of Akt is associated with severity of the tumor and metastasis. The Akt isoforms Akt1 and Akt2 are unique genes with high similarity. Recent studies suggest that these isoforms have opposite effects on breast cancer development and metastasis. With several companies and clinical trials investigating the use of Akt inhibitors in breast cancer, it is very important that we achieve a comprehensive understanding of downstream regulatory network specific to each Akt isoform.

Research Plan: The goal of this proposal is to investigate the isoform-specific role of Akt1 and Akt2 in breast cancer progression and metastasis. To this end, we will use gene expression profiles from human breast cancer tumors and analyze them using computational and statistical methods to construct a map of genes that are specifically regulated by each isoform. We will aim to identify specific targets downstream of Akt1 and Akt2 that affect breast cancer progression and metastasis. In addition, we will use clinical information available with gene expression profiles to discover genes in the Akt pathway that will effectively identify patients at high risk for metastatic progression due to aberrant signaling of the Akt pathway. We will test these candidates by detailed biochemical biological experimentation. These candidates will constitute valuable biomarkers for aggressive tumors.

Impact and Clinical Relevance: Given that Akt regulates several cellular functions and the isoforms have different roles in cancer, using drugs to inhibit Akt may be too toxic for patients. Manipulation of isoform-specific effectors of Akt activity and function may represent a means to decrease proliferation and survival of breast cancer cells, especially in patients with dysfunctional Akt signaling. Thus, our studies may lead to new advances in translational research. Several clinical trials are underway to investigate the efficacy of Akt inhibitors in breast cancer. The network generated from our studies will also aid in interpreting the results of these clinical trials.