HER2 Disease

HER2 (human epidermal growth factor receptor-2) Positive Breast Cancer

Breast Cancer Is Many Different Diseases

Researchers now understand that breast cancer is not one disease, but many different diseases. Even when tumors are classed together based on their appearance, they can act differently because of different genetic makeup. Only recently have researchers begun to understand this and to use it in predicting how a disease may progress — for example, the likelihood of a tumor to grow, spread, or recur. This is an important new area of research.

HER2-positive breast cancer is one form of breast cancer. Characterized by aggressive growth and a poor prognosis, it is caused by the overexpression of a gene called HER2 in tumor cells.

HER2 in Normal Cellular Function

Every one of the millions of cells in our body carries out its life cycle in a relatively orderly fashion dictated by its function and various other factors. The process can be altered by intra- and extra-cellular pressures that change the cell's environment. In the development of cancer, a key factor is a change in the growth rate of the cell and the ability of various control mechanisms to get the cell back on track.

The HER2 gene is responsible for making HER2 protein. When two copies of the gene are present in normal amounts, the protein plays an important role in normal cell growth and development. The HER2 protein transmits signals directing cell growth from the outside of the cell to the nucleus inside the cell. Growth factors — chemicals that carry growth-regulating orders — attach to the HER2 protein and signal normal cell growth.

Role of HER2 in Tumor Growth

In approximately 25 percent of women with breast cancer, there is a genetic alteration in the HER2 gene that produces an increased amount of the growth factor receptor protein on the tumor cell surface.

This overexpression can cause cells to divide, multiply, and grow more rapidly than normal. Research has shown that women with HER2-positive breast cancer have a more aggressive disease, greater likelihood of recurrence, poorer prognosis, and decreased survival compared to women with HER2-negative breast cancer.

It is important to understand that the HER2 gene abnormality is only present in the breast cancer cells, not in the rest of the cells in the body, and cannot be passed onto other family members.

Discovering HER2

HER2 is a normal gene; however, when amplified, it causes cancer and is called an oncogene. Many scientists had postulated that oncogenes were related to growth factors. In the early 1980s, a Genentech scientist, a British protein chemist, and an Israeli protein expert together proved that growth factors are related to cancer. They found an oncogene that was a mutated form of the epidermal growth factor (EGF) cell-surface receptor gene. By linking the study of cell-growth signals and cancer, this finding explained how an oncogene worked.

Genentech researchers then began searching for oncogenes similar to the EGF-receptor gene. They named the first one they found "HER2," for human epidermal growth factor receptor 2. With cloning technology, they discovered the protein the gene produced. They subsequently set out to find the link between HER2 and specific types of cancer. In collaboration, Dennis Slamon, M.D., Ph.D., of UCLA, looked for "matches" between the HER2 oncogene and tumor samples.

Slamon observed that the HER2 oncogene caused breast cancer cells to produce the normal HER2 protein, but in abnormally high amounts, and that the women with metastatic breast cancer whose tumor cells overexpressed the HER2 protein had an especially aggressive form of the disease. When the gene overexpresses the protein, he determined, the cell is overloaded with signals that cause it to grow out of control and become cancerous.

Taking the Biology of HER2 from Basic Research to Treatment

A Genentech research team began working on the basic science of HER2 in hopes that they could develop a potential treatment. They figured out how to transform normal cells into cancerous ones by adding copies of the HER2 gene. Next, they designed a targeted monoclonal antibody to "shut off" the HER2 gene, making the cancerous cells grow more slowly.

Antibodies are proteins made by the body's own natural immune system that are directed against foreign and infectious agents, called antigens. Monoclonal antibodies engineered through biotechnology are produced as therapeutic drugs to provide specific anti-tumor action within the body. A monoclonal antibody contains millions of identical copies of a single antibody, all of which attack the same targets.

Researchers injected samples of the monoclonal antibody into mice with tumors that overexpressed the HER2 protein. In many cases, the tumors, which were human breast cancers, shrank. The results were encouraging and researchers were anxious to test the therapy in humans. But the antibody was made of mouse protein, which might be rejected by the human body as a foreign substance. They had to figure out a way to "humanize" the antibody so the human body would accept it.

Working for more than a year, Genentech scientists developed a "humanized" version of the monoclonal antibody.