Breast Cancer Inhibitors and Disease Progression Pathway Discovered
Research finds that Akt1 plays role in metastasis and that PHLPP2 inhibits Akt1.
Researchers at the Kimmel Cancer Center have identified a protein, Akt1, that they say is key to helping one quarter of all breast cancers spread, while researchers at University of California, San Diego (UCSD) discovered that PHLPP2 inhibits this protein.
The Kimmel researchers bred mice missing the gene for Akt1, which normally plays a role in keeping cells alive by interfering with apoptosis, with other mice that overexpressed the HER2-neu (ErbB2) oncogene, which leads to approximately 25% of all breast cancers. They then examined the role of Akt1 in the onset and progression of breast cancer in the resulting offspring.
The study found that mice lacking two copies of the gene that produces Akt1 rarely had any tumors. Those mice that carried only one copy of the Akt1 gene developed some tumors, but they were small and developed more slowly. Mice with two copies of Akt1 rapidly developed significant cancer. The scientists also discovered that there was a requirement for Akt1 in metastasis.
The study also showed that Akt1 causes the cancer cells to secrete a factor, CXCL16, that promotes breast cancer cell migration. Without Akt, cancer cells failed to migrate. They also showed that deleting Akt1 completely blocked breast cancer metastasis to the lungs, while mice that expressed Akt1 died from lung metastasis. This study is reported online in Proceedings of the National Academy of Sciences.
The UCSD School of Medicine team published a study in the current edition of Molecular Cell that builds on their 2005 discovery of an enzyme, PH domain Leucine-rich repeat Protein Phosphatase (PHLPP), that is a natural tumor suppressor.
Previous research described the discovery of PHLPP, which turns off signaling of the Akt/protein kinase B. The new work describes a second family member, PHLPP2, which also inactivates Akt. However, PHLPP1 and PHLPP2 control three different disease pathways. While both are important in cancer, PHLPP 1 also impacts an important pathway in diabetes and PHLPP2 could be useful in fighting heart and neurological disease.
The researchers found that PHLPP1 controls Akt2, which is more closely involved in maintaining a constant level of glucose in the bloodstream, while PHLPP2, controls Akt1.