Centre for Functional Genomics and Human Disease

Cancer - The ETS family

Our bodies consist of a huge variety of cell types, most of which are regularly renewed throughout our lifetimes. Complex mechanisms exist which promote the development and expansion of cell types that our bodies require, and activate ‘suicide’ pathways in cells no longer required. Cancer results when these controlling mechanisms fail. For example, many cancers result when genes that induce cell growth are continually switched on. Alternatively cancer can result when the genes that activate the ‘suicide’ pathways are deleted or unable to function properly. Often both activation of cell growth and inactivation of cell death pathways have occurred, especially in patients with late disease.

The ETS family are a group of related proteins, which are master regulators of many genes. These genes include many of those responsible for the activation of cell growth and cell death mechanisms. Thus it is not surprising that abnormal ETS proteins or abnormal levels of ETS proteins are observed in some cancers.

Cancers where abnormal ETS proteins are present include Ewing’s sarcoma, B-type childhood acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and fibrosarcoma. In each of these cancers, genetic mutations have occurred which has resulted in regions of the ETS proteins being coupled to other proteins. In some cases this results in the presence of ETS in cancer cells at higher levels than normally produced. In other cases, cancer results when the new protein formed by this coupling means that the factor acquires a new biological role, inducing cell growth or suppressing cell death mechanisms.

Cancer formation may also result from increased or decreased ETS expression. Increased levels of ETS proteins have been associated with some cases of myelodisplastic syndrome, acute nonlymphoblastic leukaemia and breast cancer. Indeed, the ETS factor ER81 is present only in the estrogen/progesteron negative sub-group of breast cancers, whereas another ETS factor, ELF3, is only found in tumours that are positive for the transmembrane receptor kinase HER2/neu. In contrast the related factor ELF5 appears to be normally present in breast tissue, but is absent from many breast cancer cells.

Thus we believe that the ETS family of proteins play an important role in the development of cancer. Research at the Centre for Functional Genomics into the precise role of this family of proteins will assist in determining whether these genes can be used as markers for the development of cancer and/or as potential target for novel therapies.