The retinoblastoma gene (Rb) encodes a protein that acts by altering the activity of transcription factors. By interacting with transcription factors, Rb is able to indirectly control gene expression. In addition to this function, Rb and closely related proteins have several other less well documented activities. Ultimately, Rb and its relatives contribute to the control of the cell division process. ⁽¹⁾

The Rb gene is mutated in many types of cancer. One of the best studied is retinoblastoma, a cancer of the eye from which the gene got its name. The disease is often found in young children. Two different forms of retinoblastoma have been differentiated.

The sporadic form of the disease can affect anyone and is dependent on genetic changes (mutations) aquired during the lifetime of the affected individual.
The familial form of the disease results when affected individuals inherit a defective copy of the gene from one of their parents. In these individuals every cell contains one normal and one defective copy of the gene.⁽²⁾

As with other tumor suppressors, the cancer phenotype is not apparent unless both copies of the gene are damaged. While it is unlikely that the good copy of the Rb gene will be mutated in any given cell, the enormous number of cells in our bodies (and even an eye) make it likely that the necessary second mutation will occur. Individuals with the inherited form of the disease often suffer from many different cancerous growths, especially osteosarcomas. Other types of cancer associated with Rb mutation include lung, breast, and bladder carcinomas.⁽³⁾

A Closer Look at the Rb Gene and its Association with Cancer

The Rb gene was initially identified through its association with a familial (inherited) form of retinoblastoma. This type of cancer primarily affects the eyes and is most common in children. In its inherited form, affected individuals already have one mutated Rb gene in all of their cells and require a single mutation in the other copy to render that particular cell devoid of functioning Rb protein. Mutations are rare events and the chance of a mutation in any particular gene is rather small but the extremely large number of cells in our bodies makes it very likely that the second copy of the gene will be damaged in at least a few cells. If these cells are then able to grow in an uncontrolled manner, cancer may ensue. In cases of familial retinoblastoma, it is common for affected individuals to develop multiple tumors because of the relatively high probability of this second mutation occurring. In its sporadic form, individuals normally have two functional copies of the Rb gene in each of their cells and require two separate mutations in the same cell to lose Rb function. As a result, these individuals usually develop just one tumor. Individuals who have the familial form are much more likely to experience recurrences of tumors.

Loss of Rb activity has been identifed in osteosarcomas found in patients with familial retinoblastoma. Osteosarcomas represent nearly half of the secondary tumors identified in patients with the inherited form of the disease. Rb function has also been shown to have an influence on a woman's chance of developing breast cancer. Normally Rb regulates the G1 cell cycle checkpoint, but studies have shown that some breast cancers have a deregulation in this checkpoint, implicating Rb as a contributing factor in the disease. Rb has been implicated as a contributor to some other types of cancers also, such as, small cell and non-small cell lung cancers.

Tumor Suppressors: The Retinoblastoma (Rb) Gene

A Closer Look at the Rb Gene and its Association with Cancer