ONCOGENES

     Cells contain many normal genes that are involved in regulating cell proliferation. Some of these genes can be mutated to forms that promote uncontrolled cell proliferation. The normal forms of these genes are called proto-oncogenes, while the mutated, cancer-causing forms are called oncogenes. In contrast to tumor suppressor genes, which put the brakes on cell proliferation, oncogenes actively promote proliferation (analogous to the gas petal of the cell cycle).

Mutations that convert proto-oncogenes to oncogenes typically increase the activity of the encoded protein or increase the expression of the normal gene. Such mutations are dominant or gain-of-function mutations. Therefore, only one copy of the gene needs to be mutated in order to promote cancer.Oncogenes were first identified in oncogenic retroviruses that had picked up a cellular oncogene (c-onc) and incorporated it into the viral genome to produce a viral oncogene (v-onc). J. Michael Bishop and Harold Varmus of UCSF were awarded the 1989 Nobel Prize in Medicine for the discovery of the cellular origin of the viral oncogenes.

A. HER2/neu and breast cancer

      The HER2/neu gene encodes a receptor tyrosine kinase closely related to the epidermal growth factor (EGF) receptor (they both belong to the ErbB family of receptors). This gene is overexpressed in ~25% of breast cancers. Breast cancers that overexpress HER2/neu tend to be more aggressive clinically (more on this in upcoming lectures on Breast Cancer and Cancer Treatment). The mechanism by which HER2/neu is overexpressed is gene amplification, which results in multiple copies of the gene accumulating in tumor cells. The increase in the levels of the HER2/neu tyrosine kinase receptor on tumor cells results in increased signaling via the Ras-MAPK pathway, driving cellular proliferation. The discovery of HER2/neu amplification in breast cancer has led to the development of the anticancer drug Herceptin. Herceptin is a monoclonal antibody that binds to HER2/neu on the cell surface resulting in receptor down-regulation (decreased numbers of HER-2/neu at the cell surface) and killing of cells by the immune system. It was approved in 1998 for use in treatment of breast cancer (more about Herceptin in the Drug Development lecture).

B. Activation of Ras: the oncogene most commonly activated in human tumors

     The human genome encodes three Ras genes: H-ras, K-ras, N-ras. A large fraction of tumors contain mutations in one of these three genes. For example, 70-90% of pancreatic carcinomas contain a mutation in the K-ras gene. Ras oncogenes are activated by point mutations that result in proteins unable to hydrolyze GTP (Figure 6). These mutant Ras proteins are therefore “locked” in the GTP-bound (active) form, which therefore continually activates the MAP kinase pathway, which in turn leads to cell proliferation.

C. The Myc oncogene is often amplified or overexpressed in cancers

     The Myc protein acts in the nucleus as a signal for cell proliferation through several mechanisms. One mechanism, as discussed in the Cell Proliferation lecture, is as a transcription factor for the cyclin D gene. Myc is encoded by a proto-oncogene that is overexpressed or amplified in many cancers. Excess quantities of Myc can cause cells to proliferate in circumstances where normal cells would halt. In some cancers, rather than being amplified, Myc is made active by chromosomal translocation. (See the Cancer Cytogenetics section of the Mutation and Cancer lecture for a description of chromosome abnormalities in cancer.) As a result of this chromosomal rearrangement, a strong promoter sequence is placed inappropriately next to the Myc protein coding sequence, producing unusually large amounts of the Myc mRNA. For example, as you will learn later in this course, in Burkitt’s lymphoma a translocation brings the Myc gene under the control of sequences that normally drive the expression of large amounts of antibodies in B cells. As a result, mutant B cells produce large amounts of the Myc protein, proliferate to excess, and form a tumor.

D. Cyclin D can be activated through several different mechanisms

      As discussed in the Cell Proliferation lecture, cyclin D forms part of the G1-Cdk, which normally functions to inactive the Rb tumor suppressor protein by phosphorylating it (Figure 7). Cyclin D is often overexpressed in cancers leading to reduced activity of Rb. In breast cancer, the cyclin D gene is often amplified. As with HER2/neu amplification, this results in more cyclin E protein being produced.Cyclin D also plays a role in parathyroid adenomas, tumors of the parathyroid gland that result in uncontrolled calcium mobilization from bones (Figure 8). (The normal function of parathyroid hormone is to induce calcium release from bones). In these tumors, cyclin D can be activated by a different mechanism. A chromosome inversion places the strong transcriptional control region of the parathyroid hormone gene adjacent to the cyclin D gene on chromosome 11q. This results in the continuous expression of the cyclin D gene, which in turn promotes proliferation.In chronic lymphocytic leukemias, cyclin D is deregulated by yet another mechanism. In these tumors, cyclin D is activated via a chromosome translocation that places the cyclin D gene under control of the immunoglobulin heavy chain transcription control region. (Chromosome rearrangements are described in the Cancer Cytogenetics section of the Mutation and Cancer lecture.)