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Vol. 09 Issue 4, Fall 2004

Genetic-Environment Interaction and Breast Cancer Risk: An Exploration of Where We Stand
The Ribbon 

By Rachel Shakked

Rachel Shakked is a junior majoring in biology at Cornell. She became interested in breast cancer from her grandmother, who, while battling the disease herself, co-founded the former New Jersey Breast Cancer Coalition. Rachel researched and wrote this essay as a summer project working with BCERF under the direction of Ribbon editor Carmi Orenstein. She would like to give a special thanks to Drs. Rita Calvo, and Barbour Warren for their time spent educating her in the intricacies of breast cancer, as well as to Dr. Jeff Doyle for reading the draft.

One of the most prominent controversies around breast cancer is its causes. Some studies examine external factors such as pesticides or radiation, whereas others focus on genes associated with the disease, such as BRCA1 and BRCA2. Which has more important effect on risk, the environment or the genes?

Actually, breast cancer risk can be influenced by a complicated interaction of both genes and the environment. And complicated, as you will see, is breast cancer’s middle name. In order to fully grasp what is currently known about the disease’s etiology, we should first explore the role of genetics in the ‘everyday’ functioning of cells and breast cancer formation.

Breast Cancer: a Genetic Disease

Functions of a Normal Cell
Cell growth and replenishment are functions critical to maintaining the body’s vitality. These functions are controlled by a number of pathways, many of which might be altered in cancer cells. The body regulates this cell growth by releasing factors that control growth. Breast cells proliferate when exposed to factors such as estrogen. This usually occurs during times of breast development and when replacing old cells.

Now let’s zoom in from the big picture to the mechanisms within a cell. Most functions in a cell are carried out by proteins which make up the interacting functional parts of the pathways described above. While estrogen itself is not a protein, its effects as well as its formation are carried out by proteins. Proteins send and receive signals, copy and repair DNA, and most importantly with regard to cancer, proteins are the major players in the regulation of cellular growth through the cell cycle.

The cell cycle is controlled by a collection of signals that tell cells whether or not to undergo cell division. The signals are carried out by groups of proteins that serially activate each other in pathways that ultimately tell the cell what to do. The importance of proteins in regulating cell growth through the cell cycle is clear. But how are these critical proteins made? Like all proteins, they are made using instructions coded for by the DNA. A mistake in the DNA can mean a mistake in the protein’s shape and/or function. Therefore, the integrity of these genes plays an important role in keeping the cell cycle under control.

As growth occurs through cell division, a copy of each cell’s DNA is made so that each of the two ‘daughter’ cells has a full copy of the DNA. Very few mistakes, called mutations, occur during this process known as replication. Even if a mistake is made, cells are equipped with a surveillance system that catches and corrects most mistakes. If there are too many mistakes to be repaired, the cell can undergo cell death, or apoptosis.

How a Cell Becomes Cancerous
Sometimes a mutation gets past the close watch of the cell’s surveillance system and goes uncorrected before replication. From here on, every time the cell divides, the mistake in the DNA is reproduced and passed on to the daughter cells. When the cells are exposed to growth factors (like estrogen), they divide more rapidly, which decreases the time for DNA repair and can lead to more mutations. Eventually, there may be a family of cells with the original mutation and possibly other mutations that have accumulated as well.

It is important to note that most mutations will have absolutely no effect. This is because most human DNA is nonfunctional – it is not involved in the formation of proteins or another functional component, RNA. In addition, most mutations will occur within these regions since they make up the vast majority of space in human chromosomes. These mutations, therefore, will have no effect on cell function.

Sometimes, mutations do occur in regions of DNA that code for proteins. These mutations can end up changing the shape and possibly the function of the corresponding protein. A protein is a three-dimensional structure with a certain number of grooves or protrusions where it physically interacts with other molecules in the cell. The mutations that change the shape of the important grooves/protrusions will have the largest effect on the protein’s function. In summary, one way a protein’s function will be affected is if a mutation occurs in certain locations within the protein’s corresponding gene. These changes in structure can alter the protein’s functions in controlling cellular growth. Mutated genes can produce proteins that cannot be ‘turned on’ as well as proteins that cannot be ‘turned off.’ Both of these effects can lead to the uncontrolled growth found in cancer cells.

Some possible results of mutations that can be cancerous include:

A proto-oncogene is a normal gene whose protein products tell a cell to divide/grow by proceeding through the cell cycle. In a cancer context, it is sometimes referred to as a ‘go’ gene. When the gene is mutated to an oncogene (cancerous), the protein may be altered so that it always gives the ‘go’ signal, even when it normally should not. An example of a proto-oncogene that is explored in Box 1 is the ERBB2 or HER2 receptor gene.

A tumor-suppressor gene is a normal gene whose protein products tell a cell not to divide/grow, or to stop in the cell cycle. In a cancerous cell, one or more of these genes may have been mutated so that the proteins do not function any longer. See Box 1 for a discussion of the specific functions of p53, BRCA1, and BRCA2 tumor-suppressor genes.

Deleterious mutations in both proto-oncogenes and tumor-suppressor genes usually result in unrestricted proliferation. Therefore, the cells are constantly dividing and are more likely to accumulate further mutations when copying genetic material. Some mutations may also make the cells less responsive to surrounding cells and less responsive to the body’s signals telling the cells to stop proliferating.

In summary, breast cancer is caused by complicated accumulations of mutations in genes that code for proteins that are involved with cell growth and division. (Please see also BCERF’s Fact Sheets #5, The Biology of Breast Cancer and #6, Tumor Suppressor Genes – Guardians of Our Cells.)

Mutations can be classified into two categories: sporadic and inherited. Sporadic mutations occur by chance and very rarely go uncorrected. They sometimes occur when a cell is replicating its DNA, but are usually amended by the surveillance system. Environmental mutations are a subclass of sporadic mutations that are caused by mutagens and some carcinogens (see Box 2). Ultraviolet radiation, for example, can cause mutations in skin cells that sometimes lead to cancer. It only sometimes becomes cancerous because specific genes must be mutated for cancer to develop, as discussed above. Inherited mutations are those we obtained from our parents. They predispose individuals to cancer indirectly through interaction with other genes. The reason they are linked to cancer indirectly is because a cancer-causing gene could not be inherited since the process they alter, regulated proliferation, is extremely important during development. For this reason, many inherited cancer genes are involved with mutation repair and carcinogen metabolism. Mutated copies of these genes might predispose a person to cancer because his or her body is less capable of protecting their DNA from cancer-causing mutations.

Examples of Gene-Environment Interactions that Affect Breast Cancer Risk As described above, cancer is a genetic disease. But, the environment almost always plays an important role in altering the genes that will cause cancer. Therefore, it is easy to see that the effects of the environment on genes is not only a detail of breast cancer risk, but is the central concern (especially because it is the only thing we can do something about!).

Example 1: Genetic Susceptibility to Ionizing Radiation in 1% of the Population
An important example of how an inherited mutation can establish a cancer susceptibility to certain environmental exposures is the ataxia-telangiectasia (A-T) mutation. When the mutated form of the gene is present in both copies of a person’s chromosomes, the individual develops ataxia-telangiectasia, a rare genetic disease characterized by neurological degeneration and a greatly increased risk for cancer – 61 to 184 times higher than members of the general population (Morrell et al. 1986). Family members of A-T affected individuals seem to have an increased risk of cancer as well.

Numerous studies have shown that inheriting one copy of a faulty A-T gene increases an individual's susceptibility to the effects of ionizing radiation. It is estimated that 1% of the US, Caucasian population have one copy of the mutated A-T gene (carriers) (Swift et al. 1986). A study of 2400 people found an increased rate of cancer in blood relatives of individuals affected by A-T (Swift et al. 1991). In those women known to be carriers of the A-T mutant gene, a 5.1-fold higher risk of breast cancer was observed compared to women who were not carriers of the A-T mutation. Most importantly, environmental exposures are significant in this group. Blood relatives of A-T patients whose breasts have been exposed to ionizing radiation have a five-fold to six-fold increased risk of developing breast cancer.

Therefore, the investigators in this study conclude that ionizing radiation may increase breast cancer risk in women who are carriers of the A-T mutation. Whether or not the level of ionizing radiation used during mammography presents a risk for this group of women is yet to be determined. Genetic testing is currently available only for individuals with an A-T affected family member (Gene Tests 2004), since they have a higher chance of carrying the A-T mutation (Swift et al. 1974). The investigators also suggest that the 1% of the population that are carriers of the A-T mutation should avoid unnecessary exposure to ionizing radiation (Swift et al. 1991).

Example 2:Mammographic Density and Diet Interaction May Increase Breast Cancer Risk
Another example of genetic-environment interaction in increasing breast cancer risk was studied by Boyd et al. (2002). Breast cancer risk is increased in women whose mammograms indicate high breast tissue density (mammographic density). These scientists studied differences in the mammographic density of identical and non-identical female twins. The study concluded that approximately 63% of the differences in mammographic density can be explained by inheritance.

Boyd et al. (1997) also studied the effect over two years of a diet low in fat and high in complex carbohydrates on mammographic density. The results suggest a statistically significant reduction in mammographic density from the change in diet after adjusting for other possible contributors to the effect such as weight loss, menopause, and age. This supports the concept that a low-fat diet can affect the expression of the genes (currently undefined) controlling mammographic density. Although further research needs to be done, the possibility that environmental factors can alter the effects of a hereditary condition like mammographic density is becoming a major theme of current breast as well as general cancer research.

Example 3: Breastfeeding may reduce the level of risk presented by BRCA1
The recent finding of Jernström et al. (2004) that breastfeeding can decrease breast cancer risk in BRCA1 mutation carriers further exemplifies the importance of gene-environment interactions. This sizable case-control study (1930 women were surveyed, 685 of whom were BRCA1 carriers) reported a 45% decrease in breast cancer risk for BRCA1 carriers who breastfed for a cumulative period of more than one year.

While breast cancer risk decreased by 45% in BRCA1 carriers who had breastfed, breastfeeding has generally been shown to decrease risk to a much smaller extent for women in the general population. This suggests there is an interaction between the BRCA1 gene and breastfeeding that can decrease the elevated breast cancer risk associated with the BRCA1 mutation. These investigators speculate that the decreased risk is due to changes in mammary gland structure (differentiation) or to changes in estrogen levels during breastfeeding. (No reduced risk was found in BRCA2 mutation carriers who breastfed for any duration of time, but the sample size of BRCA2 carriers was small.) This is only one example of many interactions between BRCA1 and hormonal and reproductive factors that may increase or decrease breast cancer risk, as described by Narod (2002).

While environmental interaction with genes is suggested in all of the above examples, it is difficult to verify this relationship. For example, in BRCA1 or BRCA2 mutation carriers, the environment is necessary for cancer to form. BRCA1 and 2 are involved in the repair of double-stranded DNA breaks (Narod 2002). Smoking, ionizing radiation, and genotoxic chemicals are all mutagens that can induce double-stranded DNA breaks. But there is no direct evidence that BRCA1 or BRCA2 mutation carriers have increased risk due to these mutagen-genetic interactions. The biological link is very difficult to confirm. Therefore, there are studies designed to infer the biological link, such as twin studies.

Twin Studies as a Useful Tool for Breast Cancer Research
Fortunately for cancer research, there exist people who share some or all of their genes. Breast cancer researchers have studied twins to determine how big of a role genes, in general, play in the risk of developing breast cancer. Twin studies assume that if both twins develop breast cancer (they are concordant for the disease), the likely cause is hereditary factors. If only one twin develops breast cancer, the disease can generally be attributable to the environment. The difference in concordance between identical twins (share all genes) and non-identical twins (share about half of genes) is compared to determine the percentage of cases that result from inheritance and from the environment.

In a prominent Scandanavian twin study, Lichtenstein et al. (2000) studied 9512 pairs of twins and breast cancer (among other cancer) incidence between identical and non-identical twins. Lichtenstein’s group found that although 27% of breast cancer is attributable to hereditary factors, by far the larger number (73%) of cases are attributable to non-hereditary environmental factors, which include carcinogenic exposures from diet, lifestyle, and other aspects of the individual’s environment. These investigators note that some genes may cause cancer on their own, while other require activation by the environment. Other twin studies have explored some hypotheses such as the effect of childhood growth on premenopausal breast cancer risk (Swerdlow 2002), and whether cumulative reproductive (ovarian) hormone exposure or reproductive/hormonal milestones (like puberty, pregnancy, menopause, etc.) are important in determining breast cancer risk (Hamilton 2003).

Some Caveats with Twin Studies
Some investigators have raised concerns about the interpretation of twin studies. Relative to this discussion, the roles of the non-hereditary environment in causing disease is likely to be underestimated since populations are exposed to generally homogeneous (similar) environmental influences. In addition, genetic-environment interactions are not taken into account in these analyses. Discordant cancer cases among twins are usually interpreted as environmentally caused. But, this excludes the possibility that cancer genes that have been activated by environmental influences (such as carcinogens) may have actually caused the cancer. Finally, twin studies are often small and limited to countries that have national twin registries (like those in the Scandanavian countries). These concerns suggest an even greater role for non-hereditary environmental influences.

This article has attempted to show why breast cancer is a genetic disease, that breast cancer almost always requires environmental interaction, and some ways by which breast cancer is studied. The need for more studies of breast cancer genes and their interaction with the environment are needed. Here are a few examples of the advances that have been made as a result of studying breast cancer genetics. There are currently a number of genetic screening tests available, such as screening for mutations in BRCA1, BRCA2, and A-T genes (Gene Tests). A woman with a strong family history of breast cancer or a known BRCA1 mutation can take prophylactic actions (such as a mastectomy) and decrease her chance of getting breast cancer, sometimes by up to 90% (National Cancer Institute). Geneticists are currently able to determine the genotype of a tumor and develop the appropriate strength of treatment so as not to expose patients to unnecessary toxicity. Two recent drugs were developed as a result of studying breast cancer genetics: gleevac and herceptin (see Box 3).

With all the possible mutations and all the possible genes to be mutated, it is currently an impossible task for scientists to identify each and every genetic risk factor. The hope for using a series of mutations as markers in a simple screening for cancer is diminishing. While more and more is learned about cancer each day, science has been said to occur by baby steps. Even though the process is slow, breast cancer genetics must be studied more thoroughly. The amount we have learned about breast cancer in the past 15 years is incredible. The only way to tackle the disease is to keep learning as much as we can about it so that we can determine the best preventative measures to take.

Box 1
Proto-oncogenes code for proteins that meticulously regulate whether a cell is to enter the cell cycle, replicate its DNA, and divide. If altered, the cell may be uncontrollably instructed to replicate and divide which can begin the steps towards the growth of a tumor. A proto-oncogene is the unmutated form of the gene, whereas an oncogene is the mutated, functionally different form of this gene that can cause cancer.

ERBB2, also called HER2, is an example of a proto-oncogene. As described in BCERF’s Fact Sheet #5, The Biology of Breast Cancer, this gene codes for a receptor protein that normally binds to growth factor and signals cells to enter the cell cycle and divide. A mutated version of this gene can sometimes cause too many copies of the receptor protein, so it binds to too many growth factors and results in continuous signaling telling the cells to divide. Sometimes these receptors can release ‘go’ signals even when they are not bound to the growth factor. This could result in unrestricted proliferation of cells carrying faulty copies of this gene.

Tumor-suppressor genes code for proteins that normally restrict cell division or proliferation. When present in the normal form, the protein products of tumor-suppressor genes can prevent tumor formation.

p53 is an example of a tumor-suppressor gene that is mutated in many breast cancers, and other types of cancer. The proteins coded for by the p53 gene normally function to keep cells with damaged DNA from entering the cell cycle (See BCERF Fact Sheet #6, Tumor Suppressor Genes – Guardians of Our Cells). The gene also controls the programmed cell death function in cells that have DNA damage that is beyond repair. With a dysfunctional copy of the p53 gene, cells with damaged DNA may not be restricted from dividing, which increases the opportunity of a mutation in a proto-oncogene to be acquired and passed on.

The functioning of BRCA1 and BRCA2 are not fully understood, but the genes can act as tumor-suppressor genes. Both gene products are thought to help suppress cell growth when present in their normal form (NCI). They also function in signaling DNA repair in the cell. Therefore, when mutated, the protein products may disrupt repair of mutations that may be cancerous. Additionally, the proteins may no longer be able to suppress cell growth when there is a deleterious mutation in the DNA.

Box 2
A mutagen is any agent that causes mutations in genes. It makes sense, then, that many mutagens are carcinogens.

A carcinogen is any agent that can lead to the formation of cancer. In addition to mutagens, this includes other substances that cause cancer by a number of different methods.

Box 3
Gleevec is a novel type of drug that is a product of cancer genetics research. It is currently used for treatment of chronic myeloid leukemia and is one of the first drugs to target a specific protein that is a product of a cancer-causing mutation. Therefore, this drug targets cancerous cells and is an important early treatment for this type of cancer (NCI). Continuing genetic research on breast cancer will hopefully lead to more cancer-targeted chemotherapies like Gleevec.

Herceptin is an example of targeted treatment of breast cancer that researchers are hoping to employ. Herceptin specifically targets the protein products of the mutated HER2 or ERBB2 gene discussed in Box 1. It works by blocking the growth receptors coded for by the mutated HER2 gene so that they do not respond to growth signals (BreastCancer.org). Since Herceptin is an antibody, it can also tag cancer cells and notify the immune system to destroy them. Its effectiveness in breast cancer treatment is not established since not all cancer cells have a mutation in HER2, but the development of this type of drug is an advancement into the realm of more specific cancer drugs.

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Last Update 10.27.04