The Story of HER2
When mutated, this biochemical doorman spurs cells to divide too much.
Since humans first began recording the medical journeys of the body, we’ve known about breast cancer. The Smith Papyrus, an ancient Egyptian papyrus over 3,500 years old, records a list of four dozen illnesses, including a description of breast cancer. And yet, medical treatments with the power to treat and even cure breast cancer developed in only the last hundred and fifty years. Today, breast cancer is common. It’s a disease of the people, responsible for 25 percent of female cancers, worldwide, today and the most common cancer in American women, with 1 in 8 expected to develop invasive breast cancer in their lifetime. For a while, the fight against breast cancer was decidedly one-sided. Until 1976, we were groping with scalpels in a race to stop the march of the tumors, trying blindly to halt breast cancer’s riot in the body. But that year, something changed: We discovered oncogenes.
Normally, genes direct the cell in a systematic way, turning “off” and “on” in controlled ways that promote healthy growth and development. However, certain genes have an inherent ability to cause trouble – cancer – with only a few changes to the DNA that encodes it. These genes that have the potential to cause cancer are known as oncogenes. And it is the discovery of these genes that revolutionized the way we looked at cancer proliferation and treatment.
Once we realized that our own cells carried cancer instructions, scientists in the late 1970’s developed a process to see if these recently discovered oncogenes might be more active in cancer, and, sure enough, while polyester and cocaine fueled a disco nation, these intrepid researchers hit upon a likely culprit: the HER2 gene. And it changed everything. So much so that today, modern survival rates for breast cancer in wealthy countries are high, with between 80 percent and 90 percent of patients diagnosed with the disease in the United States and England surviving at the five-year mark. And this is, in no small part, due to how we’ve learned to exploit the rogue activity of the HER2 gene.
HER2 is known by several names: receptor tyrosine-protein kinase erB-2 if you prefer the mouthful; ERBB2 for the rest of us. This gene instructs cells how to form receptors on the cell surface; these receptors play a key role in controlling cell growth and division. When a gene is turned on, it’s is being “expressed”; the state of a gene being is “on” too much is known as overexpression. Overexpression of the HER2 gene, has been linked to the development and progression of certain types of cancers, specifically, breast cancer, in which around 1 in 3 tumors carry this important biomarker.
In healthy tissues, the HER2 gene helps drive many critical cellular responses, functioning as a biological messenger of sorts. It mans the biochemical switchboard responsible for changes in how and when certain genes are expressed, as well as the rearrangement of structural elements within the cell (important for cell replication), if and when the cell self-destructs, and how the cell proliferates (makes more of itself). Furthermore, when inside the nucleus, HER2 is important for transcriptional regulation; that is, which genes are expressed, and when. Which, it turns out, is a non-negotiable need.
The genes in your body are not constantly turned on (expressed); this is great if you, like the rest of us humans, only need to go through the explosive growth of fetal development but once. To wit, if a newborn continued to grow at the rate at which it grew at birth, it’d be as tall as the average American male by the time it was around two and a half. So yes, regulating how genes are expressed, and to what extent, is vital to the body’s general ability to self-regulate and stay healthy.
Which is why, when the genes responsible for such important tasks go awry, the results can be significant. Over-expression of the HER2 gene occurs in 15 percent to 30 percent of breast cancers, and is associated with disease recurrence and a poor prognosis; however, that said, we have drugs to target this specific mutation, and generally speaking, persons with HER2-positive tumors have better long-term outcomes than those without. Amplification of this gene is also known to occur in ovarian cancer, stomach cancer, aggressive forms of uterine cancer, as well as tumors from the small bowel, esophagus, kidney, and mouth.
The calling card of HER2 mutations are changes that herald uncontrolled cellular growth; basically, these mutations allow affected cells to replicate faster, and stay alive longer than regular cells, resulting in cells that outcompete their neighbors: in a word, cancer. One study found that around 1 in 4 breast cancers tumors had a blatant excess of HER2 receptors; the standard is around 20,000, but in cells expressing the mutation, there were upwards of two million of the receptors for which the gene codes, causing these cells to receive tens of thousands signals to reproduce and replicate out of control. HER2 proteins have also been seen forming clusters in the outer membrane of the cell, a feature that may play a role in tumorigenesis. But it’s not just quantity: when it comes it HER2, quality definitely plays a role.
One of the ways cells send and receive message is through a chemical process called ligand-binding, wherein the receptor on the surface of the cell must bind to a specific molecule to kickstart the conformational change that heralds the signaling of a certain action, be it replication, apoptosis (cell death), or many other instructions dictating the proper course of biological action. However, HER2 can’t just outright bind to a ligand; it apparently needs a buddy, or “colocalizer” to help it bind, called GRB7. This colocalizing friend is a proto-oncogene, meaning that it’s a normal gene that can easily transition into a cancer-causing gene with a few edits.
But that’s when everything is working as it should. A few structural alterations to the HER2 protein have been found to result in the receptor firing without the ligand. This means that with a few small changes to the HER2 gene, the resulting protein doesn’t need outside instructions to give the go-ahead signal for replication. In fact, the substitution of even a single incorrect building block at a specific site in the protein can result in a receptor that is always “on”, no matter what the HER2 protein is – or isn’t – bound to. And uncontrolled cellular growth is the beginning of a tumor.
Because researchers have identified the biochemical doorman that is HER2, cancers bearing this important molecular marker have a variety of treatment options that those without do not
In 1998, the HER2-targeting antibody trastuzumab was approved to tackle mutations that over-express the gene in breast cancers. This drug, known by its non-generic name “Herpectin” blocks the chemical signals to the HER2 receptor, staunching the flow of uncontrolled cellular growth that results from mutations in this critical receptor. Since breast cancer cells with too many HER2 growth receptors are able to receive an excess of signals, this leads to an pathological uptick in cell growth and multiplication; blocking this pathway, then, is akin cutting off communications to the signals, to keep cancerous cells from spilling into circulation. The drug in question blocks relevant receptors on the cell’s surface, keeping the HER2 doorman from receiving and acting upon the growth signals that float through the biological soup that bathes the cell.
This is not to say the battle is won; despite these new and exciting treatment options for HER2-positive cancers, most patients with breast carcinoma still rely on chemotherapy for a critical part of their treatment, alongside these new drugs. Studies suggest that over-expression of HER2 can lead to increased resistance to certain chemotherapeutic drugs, further underscoring the need to test breast cancers for this important biological quality.
However, there are other promising treatment options in the race to develop drugs that specifically target HER2-positive cancers, such as gene therapy, single-chain antibodies, and tyrosine kinase inhibitors, the latter of which is a class of drugs that act on the molecular family to which HER2 belongs. It is the hope of researchers that HER2 gene defects can be exploited to stop the riot of cancer in the body.
Treatments options for HER2-positive mutations
Testing for HER2 mutations involves DNA analysis of tumor tissues. The HER2-targeting antibody trastuzumab (marketed as Herceptin) is approved to tackle mutations in this gene. It does so by blocking the chemical signals to the HER2 receptor, staunching the flood of over-expression. Since breast cancer cells with too many HER2 growth receptors receive an excess of signals, blocking this pathway keeps the HER2 receptor from receiving and acting upon growth signals.
There are other promising treatment options in the race to develop drugs for HER2-positive cancers, such as gene therapy, single-chain antibodies, and tyrosine kinase inhibitors. However, most patients with breast carcinoma still rely on chemotherapy for a major part of their treatment, supplementing their care with novel treatments to address their specific HER2 mutation. Additionally, there is evidence that over-expression of HER2 can lead to increased resistance to certain chemotherapeutic drugs, underscoring the need to test relevant cancers for this critical biological marker.