Novel Akt Regulatory Factor PHLPP in Breast Cancer

Institution: University of California, San Diego
Investigator(s): Noel Warfel, M.S. -
Award Cycle: 2009 (Cycle 15) Grant #: 15GB-0018 Award: $0
Award Type: Dissertation Award
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2009)

Internal breast cancer cell signaling pathways control the balance between death and survival. When these pathways become altered compared to normal cells, normal cell division and growth increases, leading to cancer. One of the most important and prevalent signaling pathways activated in breast cancer is the Akt pathway. Akt drives the formation of many types of cancer, including breast cancer unless its activity is tightly monitored. PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) is an Akt-regulatory protein (residue S473 dephosphorylation) that serves to inhibit the intrinsic catalytic activity of Akt. We have identified a novel mechanism through which cells stabilize PHLPP in response to Akt activation, ultimately providing a feedback loop to inhibit Akt signaling. If this mechanism is lost in breast cancer, it could explain why many breast tumors have highly active Akt.

The goal of this dissertation research project is to determine the biological mechanisms that control PHLPP activity and stability. In order to measure the activity of PHLPP, we have developed a technique to assess the ability of PHLPP to turn off Akt signaling. We plan to use this technique to determine how PHLPP activity is altered in response to signals that promote cell growth, similar to those present in the breast tumor environment. These experiments will help us to understand how PHLPP activity is controlled and whether there are differences between normal and breast tumor cells. Next, the ability of PHLPP to terminate Akt signaling may also depend on the amount of PHLPP present in cells. We will determine whether PHLPP activity and/or stability are altered in breast cancer vs. normal breast cells. Finally, we plan to identify the protein(s) responsible for targeting PHLPP for degradation by utilizing a high throughput screening technique. This line of research has the potential to identify a novel protein that controls the stability of PHLPP, and possibly an independent target for breast cancer therapy.

Although Akt signaling is one of the most heavily studied pathways in cancer research, little is known about how Akt is turned off. The very recent discovery of PHLPP in our laboratory has opened-up a novel research avenue. Understanding PHLPP regulation is important to the field of breast cancer research because it directly blocks a signaling pathway that is vital to progression of the disease.