How BRCA Genes Work

That's a breast cancer cell as captured by a scanning electron microscope, which produces a 3-D image.
That's a breast cancer cell as captured by a scanning electron microscope, which produces a 3-D image.
Image courtesy Bruce Wetzel and Harry Schaefer)/The Web site of the National Cancer Institute

Thanks to a 2013 New York Times op-ed, we all know about Angelina Jolie's decision to have a preventive double mastectomy to reduce her risk of developing future breast cancer. Her candid comments revealed that she has both a strong family history of the disease and, based on the results of genetic testing, a mutated form of the gene known as BRCA1, which gives her an 87 percent chance of breast cancer and a 50 percent chance of ovarian cancer [source: Jolie]. Faced with this reality, which can be more or less severe for different people, she chose to remove both breasts before the cells making up her milk-producing glands could turn into rogue cancer cells capable of uncontrolled growth.

If the procedure protects her from this disease, as probability suggests, she'll have lots of people to thank: the genetic counselors, the surgeons, and her family, of course, to name a few.

Mary-Claire King may not make that list. A professor of genome sciences and medical genetics at the University of Washington, King helped to unravel the genetic basis of inherited breast cancer. Her work led first to the discovery of BRCA1 in 1994 and then, a year later, to BRCA2. Women (and men, too, as it turns out) who carry mutated forms of these genes are far more likely to develop a number of cancers, including breast, ovarian and prostate cancer.

King herself often points to another VIP -- Paul Broca, a French pathologist who first proposed in the 1860s that breast cancer might run in families. Broca's wife suffered from early-onset breast cancer, and when he studied her family tree, he found that the disease could be traced back through four generations. When King went to name the gene she had discovered, she wanted to call it BROCA to honor the Frenchman, but she was only allowed four letters. The final name -- BRCA -- abbreviates "Broca" while standing for "breast cancer" and perhaps even Berkeley, Calif., where King did her doctoral work [source: Check].

Nomenclature aside, the BRCA genes stand as a success story of modern genetics, proving that biomarkers can reliably predict a person's predisposition to develop a disease or condition. A decade or so ago, buoyed by the success of the Human Genome Project, forward thinkers promised a time when biological molecules found in the body would serve as indicators of phenomena such as disease, infection or environmental exposure. These signallers would lead to the eradication of cancer and other pernicious conditions. But a funny thing happened on the way to utopia: Biomarkers proved challenging to identify. And when they were, researchers couldn't develop assays sensitive enough or cost-effective enough to make them valuable diagnostic tools.

So the medical community welcomed the discovery of the BRCA genes, and the development of reliable genetic testing to identify them in individuals, with open arms. All of which has led to the next challenge: making sure the public understands what these genes are.

Breast Cancer Basics

Breasts are amazing structures. They're so unique in the animal kingdom that their presence defines an entire group of organisms -- the word "mammal" comes from "mammary," which itself comes from "mamma," the Latin word for breast, udder or teat. Biologists would classify breasts as exocrine glands, or structures that secrete their products through ducts to the external environment. This isn't the same as endocrine glands, which secrete their products directly into the bloodstream.

The product made from breasts, of course, is milk. Milk arrives to the outside world through the nipple, but it begins its life deeper in the breast, in clusters of cells known as alveoli. These clusters form lobules, which themselves create larger structures known as lobes. As the alveoli produce milk, the fluid passes through thin tubes -- lactiferous ducts -- that lead to openings in the nipple. Fibrous tissue and fat fill the spaces between the lobules and the ducts, and the whole structure sits on top of the pectoralis muscles of the chest. A network of lymph vessels and nodes surrounds all of this tissue and extends upward into the armpit.

In many women, this tissue functions properly and never causes problems. Next, though, we'll look at what happens when it does.

Acquired Mutations: HER2- and Estrogen-positive Cancers

A medical illustration shows a cancerous tumor within the female breast.
A medical illustration shows a cancerous tumor within the female breast.
© Visuals Unlimited/Corbis

Sometimes the cells making up breast tissue can begin to grow unchecked, crowding out normal milk-producing cells. As these uninhibited bullies push and shove their way around, they form a mass of tissue known as a lump or tumor. If the lump stays contained and doesn't invade surrounding lobules or other parts of the body, it's classified as benign. If, however, it continues to invade the surrounding breast and spreads to the lymph nodes, it's classified as malignant or cancerous.

Scientists now know that cancer is caused by damage to DNA -- a mutation -- in genes that regulate cell growth and division. Many mutations arise when someone is exposed to certain environmental conditions, such as radiation. Breast cells are not immune to these acquired (as opposed to inherited) mutations. In fact, two types of breast cancer occur when DNA becomes damaged as a result of environmental carcinogens or viruses.

The first type affects how hormones, like estrogen, interact with breast cells. During a woman's monthly menstrual cycle, estrogen levels surge in the breast to prepare the tissue to make milk. Estrogen molecules bind to receptors in the breast cells, triggering the cells to proliferate. If a woman doesn't become pregnant, all of these extra milk-producing cells deteriorate and die. Sometimes, though, this proliferation process can go haywire if certain breast cells harbor damaged DNA. When these compromised cells receive the signal from estrogen, they multiply as they should, but they fail to stop and don't die at the end of a cycle.

Another acquired mutation affects the gene coding for a protein known as human epidermal growth factor receptor 2, abbreviated HER2. Normally, HER2 proteins on the surface of breast cells respond to growth factors -- chemicals that tell a breast cell how to grow properly. HER2 proteins receive these factors, then shuttle the instructions inside the cell. If the DNA of the HER2 gene becomes damaged, however, its activity can rev up to dangerous levels. It can produce too much HER2 protein and, as a result, cause unchecked growth of breast cells.

Neither estrogen-positive nor HER2-positive cancers can be passed on to other family members because the mutations affect only breast cells. That's not the case with inherited breast cancer. In this form of the disease, a mutation is carried in a parent's sperm or egg cells and passed, at fertilization, to his or her offspring. These mutations then appear in every cell of the body and predispose the person to developing cancer. Scientists have discovered several genes linked to inherited breast cancer, including the acronym nightmares p53, PTEN/MMAC1, CHEK2 and ATM. But the BRCA genes are the best known and perhaps the most intensely studied. In the next section, we'll take a closer look at the family tree of BRCA genes.

The BRCA Gene Families

Thanks to Watson, Crick and thousands of others, we know a lot about the chemical basis of heredity. In case you've forgotten or blocked it from your memory, recall that the nucleus of a human cell contains chromosomes -- the threadlike structures carrying all of our genetic information. Human cells have 23 pairs of chromosomes, for a total of 46. Each chromosome consists of a DNA double helix bearing a linear sequence of genes, coiled around proteins known as histones. A single gene is a distinct sequence of nucleotides, the building blocks of DNA, that codes for a corresponding protein.

As scientists hunkered down over the human genome, they noticed that some genes shared certain characteristics. They either carried a similar sequence of nucleotides, or they were dissimilar genes that produced proteins capable of participating in the same cellular process. They grouped these genes into families and then used the classification system to predict the function of newly identified genes based on their similarities to known genes.

There are two BRCA genes -- BRCA1 and BRCA2 -- and each belongs to a different family. BRCA1 belongs to the RNF family of genes, which code for proteins known as RING-type zinc finger proteins. These proteins are so named because the protein molecule has regions that fold around a zinc ion and because the resulting shape of such a region resembles a finger. The unique shape of RING-type zinc finger proteins enables them to bind readily with other molecules, especially proteins and nucleic acids. Once they're bound to another molecule, they perform some enzymatic action that helps a cell maintain a stable environment. Some of these activities include cell growth and division, signal transduction, protein degradation and, as we'll see in the next section, tumor suppression.

BRCA2 genes belong to the FANC gene family. Genes in this group produce a complex of proteins that participate in a process known as the Fanconi anemia (FA) pathway. This pathway primarily works on locating and repairing DNA damage. In particular, the proteins target sections of DNA where the opposite strands of the double helix are not properly linked. When they find such an area, the FANC proteins bind to the DNA and rebuild the cross-links, allowing the DNA to replicate and function normally.

Clearly, the RNF and FANC gene families play important roles in keeping us healthy. If something interferes with the function of these genes, it can lead to a number of diseases. For example, disruption of RNF genes can lead to myotonic dystrophy, which is characterized by progressive muscle wasting and loss. Disruption of FANC genes can result in, you guessed it, Fanconi anemia, which can cause bone marrow failure, physical abnormalities and organ defects. And, of course, both gene families play a role in certain cancers, including breast cancer.

Up next, we'll look very specifically at BRCA1 and BRCA2 to understand how they function normally and how mutations to the genes lead to breast cancer.

BRCA Gene Basics

A snapshot of what chromosome 17 -- home of BRCA1 -- might look like.
A snapshot of what chromosome 17 -- home of BRCA1 -- might look like.
Illustration courtesy William Harris

Mary-Claire King may have wanted to honor Paul Broca by naming BRCA after him, but modern geneticists know the genes by their official names: "breast cancer 1, early onset" and "breast cancer 2, early onset." You may also hear "breast cancer susceptibility genes 1 and 2" or "hereditary breast cancer 1 and 2." With such similar names, you might think the two genes reside together on the same chromosome. That's not the case. The exact location of BRCA1 is 17q21; BRCA2 is 13q12.3. Here's what those numbers mean:

  1. The first number indicates the chromosome, which means BRCA1 can be found on chromosome 17, BRCA2 on chromosome 13.
  2. All chromosomes have a short arm, p, and a long arm, q, so both BRCA genes sit on the long arms of their respective chromosomes.
  3. When scientists stain chromosomes, genes appear as light- and dark-colored bands, which themselves are organized into regions. A two-digit number indicates the region followed by the band. A decimal reveals a sub-band. BRCA1, then, is located on region 2, band 1. BRCA2 is located on region 1, band 2, sub-band 3.

Even though BRCA1 and BRCA2 belong to different gene families, they both produce large proteins that participate in tumor suppression when they're working normally. The BRCA1 protein consists of 1,863 amino acids and BRCA2 of 3,418 amino acids [source: van der Groep]. The BRCA1 protein exerts its tumor suppression effects by collaborating with a number of other proteins to mend breaks in DNA. These BRCA1 protein complexes likely affect several DNA repair processes, including homologous recombination (swapping a sequence of nucleotides with another similar strand of DNA), nucleotide-excision repair (cutting out damaged DNA bases and pasting in new ones) and non-homologous end-joining (stitching a double-strand break back together). The BRCA2 protein also participates in DNA damage control, but appears to be much more limited. Scientists think the BRCA2 protein regulates the activity of a smaller number of companion proteins, including RAD51 and PALB2, to direct homologous recombination of damaged DNA.

Now imagine what would happen if you removed BRCA genes from a cell or threw a monkey wrench into their molecular machinery. Without their associated proteins, several DNA repair processes would cease to function and, over time, as cells were exposed to radiation or chemical agents, more and more defects would accumulate. These mutations would eventually cause cells to go wonky and become cancerous.

This is exactly what happens when BRCA genes become compromised. A mutation to one of the genes scrambles its instruction manual. As a result, the gene no longer has the ability to build correct versions of its related protein. The protein may be abnormally short or may not have the correct sequence of amino acids. These defective proteins can no longer participate in the DNA-repair process, which eventually leads to the proliferation of cells carrying damaged DNA. If these cells line the milk ducts of breast tissue, a lump or tumor, created by a mass of abnormal cells, may develop there. In addition to breast cancer, BRCA mutations can also lead to ovarian cancer, fallopian tube cancer, pancreatic cancer and prostate cancer.

Unfortunately, nature has found lots of ways to disrupt the BRCA genes. To date, scientists have identified more than 1,000 mutations in the BRCA1 gene and more than 800 mutations in the BRCA2 gene [sources: Genetics Home Reference, Genetics Home Reference]. And remember, these defective genes can be passed from one generation to the next, which means people who inherit the mutation carry it with them their whole lives. It sits in their cells, going unnoticed until a cancer develops or until someone takes steps to prevent that from happening. That's where genetic testing comes in.

Testing for BRCA Mutations

Learning about BRCA mutations can make anyone anxious. It's easy to think you might be susceptible to cancer because you carry one of the defective genes. In reality, only about 5 to 10 percent of all cases of breast cancer in the United States are due to inherited gene mutations [source: Susan G. Komen for the Cure]. That means almost all breast cancers develop as a result of spontaneous or acquired mutations unrelated to heredity. Most women, therefore, would not benefit from genetic testing.

How do you know? The following guidelines can help you decide whether to pursue testing for BRCA gene mutations. You should consider testing if you meet any one of the following criteria, as proposed by Susan G. Komen for the Cure, a nonprofit dedicated to ending breast cancer through research, community outreach and advocacy:

  • You were diagnosed with breast cancer at an early age.
  • Your mother, sister or daughter was diagnosed with breast cancer at an early age or ovarian cancer at any age.
  • A woman in your family, including first- and second-degree relatives (mother, sister, daughter, grandmother, aunt), has had breast and ovarian cancer.
  • Your mother, sister or daughter was diagnosed with breast cancer in both breasts.
  • Your family is of Ashkenazi Jewish descent.
  • A male in your family has had breast cancer.

A simple test can reveal whether or not the mutation exists in your cells. In most tests, a technician will take a sample of your blood. In other tests, you use an oral rinse. Each method allows the testing facility to obtain cells -- and genetic material -- from your body. At a laboratory, scientists analyze this material to look for changes in the actual BRCA genes or in the proteins coded by these genes. The testing takes three or four weeks and can cost several hundred or several thousand dollars.

If you receive a positive test result, then you know you've inherited a known mutation in BRCA1 or BRCA2. And having a BRCA mutation greatly increases your cancer risk -- up to 50 percent to develop breast cancer by age 50 and up to 87 percent to develop breast cancer by age 70 [source: Myriad Genetics]. A genetic counselor can help you assess this risk and decide what course of action to take. One option, of course, is to maintain vigilance with routine mammograms and clinical breast exams, with the goal of detecting a cancer early, when it's most treatable. Another option involves taking medications, such as tamoxifen, to reduce the risk of developing cancer. And, finally, you can take Angelina Jolie's lead and opt for prophylactic surgery -- removing as much of the cancer-susceptible tissue as possible.

There are no guarantees, however. Even with a preventive double mastectomy, breast cancer can still develop if the surgery failed to remove all of the at-risk tissue. And yet this modern era of genetics-based medicine has led to a true revolution in breast cancer detection and treatment, which is why, since 1990, there has been a 33 percent decline in breast cancer mortality in the United States [source: Susan G. Komen for the Cure].

Author's Note: How BRCA Genes Work

The breast cancer story is amazing on many different levels -- the science behind the discovery of the BRCA genes, the stunning increase in survivorship and the candor with which we all now speak about the disease. But what amazes me even more is the outrageous complexity of our cellular machinery, with DNA zipping and unzipping and protein complexes assembling to keep our genetic information intact and functional.

Related Articles


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