HER Pathway

Surpassing heart disease in 2004, cancer is now the leading killer in the United States. According to the American Cancer Society, more than 1,500 people die each day from cancer and over 16 million people have been diagnosed with cancer since 1990.

In recent years, medical science has taken great strides in understanding and treating cancer. However, prior to 1997, the majority of treatments such as chemotherapy and radiation, were not based on the underlying biology of cancer growth. These treatments are also often associated with serious side effects.

Since the discovery of the HER2 gene, researchers from around the world have elucidated that HER2 is a main component of a complex signaling pathway that includes numerous family members, many of which are also involved in the formation of cancer and other diseases.

Cancer Growth and the Genesis of Cancer

Cancer begins when the DNA of a normal cell changes, or "mutates", making normal cells grow uncontrollably.

There are two types of mutations:

  • Somatic mutations, which are caused by environmental factors such as sunlight or carcinogens; and
  • Hereditary cancers, which are harmful mutations passed down from one generation to another.

Each type of mutation eventually "expresses" itself by producing chemical signals within the cell that tell the cell to grow. The cell then enlarges, divides and reproduces itself, creating two new identical copies of the original. In normal cells, growth occurs at a steady, regulated rate. In cancer cells, growth is unregulated and continues as long as the tumor obtains the requisite nourishment it needs from the surrounding environment.

Communication by Signal Transduction

Signal transduction is a means by which one cell communicates to another. The "conversation" between two cells involves a molecular messenger (called a ligand) from the sender and a site (called a receptor) on the membrane surface of the cell receiving the signal. When the signal is received, it is passed along within the cell in the same way a bucket of water might be passed along a bucket brigade. In this way, the message is communicated from the outer surface of the cell into the cell's nucleus. Messages can be healthy or harmful. For example, some messages might be signals telling the cell to grow (which can lead to cancer) or a growth signal might be used by the immune system to increase the amount of white blood cells needed to fight and infection. In other cases, signals may cause cells to store materials such as fatty acids, which is healthy in moderation but when uncontrolled, may lead to obesity. This process is referred to as signal transduction.

Some of the more common signaling pathways involve proteins called receptor tyrosine kinases, which have three components:

  • An extracellular ligand-binding domain receptor that is located outside the cell and receives incoming signals;
  • A transmembrane domain that crosses the cell membrane and conveys information from the outside to the inside; and
  • An intracellular tyrosine kinase domain that adds a phosphate molecule to tyrosine, a type of protein. This process initiates an internal messaging cascade and is referred to as "phosphorylation."

Introduction to the HER Pathway

In oncology, one of the most important tyrosine kinase signaling networks is a group of receptors belonging to the "HER" family, also known as the ErbB signaling network. The ErbB receptors are named after the Avian erythroblastosis tumor virus, which encodes an aberrant form of the human epidermal growth factor receptor (from which "HER" originates).

The HER family of receptors consists of four main members commonly referred to as HER1/EGFR, HER2, HER3 and HER4. Each of these receptors is in some way culpable in the development of malignant tumors, although some are more involved than others. There is a considerable amount of "cross-talk" between the receptors, meaning that activation or inhibition of one can have collateral effects on the others.

Understanding the biological role of the HER family has led to the discovery of other important signaling systems, such as receptors that are distinct from the HER family but have the ability to "quiet" HER-generated tumor-stimulating signals.

One of many important discoveries resulting in an exploration of the HER-based signaling pathways includes the PTEN gene, which appears to be abnormal in as many as 50-60 percent of advanced prostate cancers. PTEN is thought to be a tumor-suppressor gene, and works in complete opposition to the HER genes although it uses the same signaling pathways. Unlike kinases, which make cells grow, the PTEN gene produces an enzyme called a phosphatase, which halts cell growth. The PTEN phosphatase regulates growth in a common signal transduction pathway activated by receptor tyrosine kinases.

Identifying the Source of Dysfunction

In all cells, some level of growth-signal transduction is normal and is part of the regular growth cycle. It is the overexpression, or activation, of these signals — or the failure to counterbalance or block those signals — that leads to uncontrollable growth. In the case of the HER2, for example, overexpression is the result of a genetic alteration that generates multiple copies of a gene that encodes a growth receptor. Because of the surplus of growth receptor genes in the cell, excessive numbers of growth receptors are created that, when activated, enlarge the number growth signals stimulating the cell, accelerating cell division and tumor growth.

Key Players in the HER Pathway

The four members of the HER family are called HER1, HER2, HER3 and HER4. Each is implicated in the development of cancer although the degree of involvement varies.

Name Other Names Type(s) of Dysregulation Cancer Types
HER1 EGFR Overexpression
Mutation leading to constitutive (non-stop) activity
Head and neck, bladder, prostate, renal, non-small-cell lung cancer, ovarian, pancreatic and glioblastoma.
HER2
c-erbB-2
ErbB2
Overexpression
Co-expression with HER-1 improves ability to predict aggressiveness of breast cancer
Breast, ovarian
HER3 ErbB3 Co-expression with HER-2 improves ability to predict aggressiveness of breast cancer Breast, colon, gastric, prostate, other carcinomas
HER4 ErbB4 Reduced expression produces differentiated phenotype
Co-expression with HER-2 has prognostic value
Breast, prostate,
childhood medulloblastoma

A Closer Look at the HER Pathway Players

An physical feature of the HER pathway is that the signaling system always involves two receptors in combination, in a formation called a "dimer." Homodimers are combinations of two similar receptor types, such as HER1/HER1 and HER3/HER3. Heterodimers contain two different receptors, such as HER1/HER2; HER1/HER3; and HER4/HER3. The various hetero- and homo-dimer pairs affect the signal strength within the cell. For example, the co-expression of certain pairs (such as HER3/HER2) is more powerful than others such as the HER3/HER- homodimer, which is inactive. Research is underway to better understand why certain pairings have different effects and how those effects manifest themselves.

HER1/EGFR

Another abbreviation for the human epidermal growth factor receptor is EGFR, a name that is often used due to the observation of clinical benefits associated with its inhibition.

HER1 overexpression enhances tumor cell motility, adhesion and metastatic potential while normal HER1 signaling disrupts cell cycle control (leading to proliferation) and apoptosis (programmed cell death).

HER2

Perhaps the best-known member of the HER family, overexpression of the HER2 gene is correlated positively with an especially aggressive form of breast cancer that occurs in approximately 25 percent of all breast tumors. HER2 also is overexpressed in a variety of other solid tumors and may interact with certain steroid hormone networks, suggesting that it could affect patient response to anti-estrogen therapies.

HER3

Expression of HER-3, when activated in a conjunction with HER-2, is linked to increased tumor aggressiveness.

HER4

Some studies have shown a lower expression of HER-4 in breast and prostate tumors relative to normal tissue.

Future of Cancer Therapy and the HER Pathway

Having established the HER pathway's role in a variety of solid tumors, molecular-targeted therapies are a valid and rationale approach to cancer treatment. Scientists are now utilizing the underlying biological mechanisms involved in cancer growth and metastases to develop clinical strategies to treat patients with cancer. While researchers continue to study the biological inner-workings of the HER pathway and other pathways involved in cancer, Genentech clinicians and collaborators are using the acquired knowledge to identify new and innovative ways to treat cancer patients.

Since certain receptors in the pathway work together to produce malignancy, one of the clinical strategies being explored today involves the possibility of combining several targeted HER molecules as well as other targeted therapies into a single treatment regimen - based on the biology of disease - that potentially have a synergistic or additive effect on the tumor and could on day lead to cancer becoming a more chronic disease.

HER Pathway Timeline

1980 - Discovery of EGFR (earliest review article)
1985 - Discovery of HER2 gene's distinctiveness from HER1
1985 - Characterization of the Promoter Region of the Human c-erbB-2 Protooncogene - Proceedings of the National Academy of Science
1987 - HER2 linked with breast cancer
1987 - Human Breast Cancer; Correlation of Relapse and Survival with Amplification of the HER2/neu oncogene