Genetic, Epigenetic and Tissue Organizational Effects
Changes in Cell Processes
Cancer cells are cells that behave differently than normal, healthy cells and tissues do. For a long time, cancer was thought to occur because of mutations in the genes (DNA) in individual cells. Newer understandings suggest that the picture is more complex.
Although we have much yet to learn about genetics and how cells interact with one another and with our environment, we know that the story of breast cancer and genetics isn't as simple as having the "breast cancer gene" or not.
Emerging research shows that while a variety of gene mutations may influence cancer risk, environmental factors may influence whether those mutations express themselves as cancer or not. We're also seeing that cells do not live in isolation, but rather communicate with and influence each other—intercellular communication that can also affect cancer risk.
This animated video, produced by Vassar College's Environmental Risks of Breast Cancer project , explains how normal cells are transformed into cancer cells, also known as carcinogenesis.
We understand clearly now that various factors, whether related to environmental, genetic, lifestyle or reproductive histories, all interact to create the particular disease risk profile for an individual person. Even the term genetic or “gene-related” can involve a variety of processes, and these are always being expressed in the larger context in which the individual develops and lives. Genes and the function of their protein products are regulated within the context of highly complex cellular systems, each of which, in turn, interacts with hundreds of neighboring cells, all communicating closely with one another and influencing each other’s structure and function.
It is estimated that between 5 and 10 percent of all female breast cancers are the result of mutations in the primary nucleotide sequences of genes inherited from one's parents. The most common and best studied of these so-call germline mutations are BRCA1 and BRCA2, both of which belong to the broad class of “tumor-suppressor genes.” So, for example, among the various functions that BRCA1 regulates are those related to DNA repair (Oldenberg, 2007).
Inheritance of a mutated form of either of the BRCA genes, or of other less common tumor-suppressor genes that have been associated with breast cancer, is associated with a very significant increase in risk for breast cancer. Yet not all women (or men) with BRCA mutations develop breast cancer. One factor that may influence ultimate risk is the site where the mutation lies on the actual gene (del Valle 2009; Bradbury 2007). Other factors, such as early exposure to environmental chemicals and/or radiation, may also influence later expression of genetic irregularities (King, 2003).
In addition to these primary mutations in tumor-suppressor genes, recent scientific evidence indicates that structural alterations in other genes, such as those involved in hormone synthesis and breakdown, may increase susceptibility for later development of breast cancer. Other genes may work in concert to affect regulation of cell-cycle and DNA-repair processes, and mutations in one or more of those genes may alter susceptibility to other genetic, lifestyle, hormonal or environmental challenges (Bradbury, 2007; Conde, 2009; Silva, 2009). Increasingly, data are demonstrating that the complexity of individual genetic profiles may help explain some of the differential sensitivity to environmental factors, as well as hormonal and lifestyle factors, when it comes to predicting risk for later disease (Ghoussani, 2009).
When genes are expressed, a series of steps is initiated within the nucleus of the cell that leads to the synthesis of new proteins. These proteins may be enzymes (catalysts for metabolic and other cellular activity), structural proteins (important for the physical integrity of the cell) or receptors (proteins that interact with, among other things, hormones to induce changes in cell activity). Regulation of the expression of a particular gene is influenced by many different factors, all of which determine the health and viability of the cell and, ultimately, its flexibility in responding to different factors, both internal (e.g., nutritional and hormonal) and external (e.g., environmental chemical).
Figure 1: One kind of genetic change that can lead to tumor growth emerges from changes in the basic code for genes. Genes are made up of base pairs of four different molecules called nucleotides: adenine, cytosine, guanine, thymine. The names for these are often shortened to A, C, G, and T. A always pairs with T, and C always pairs with G. This means that even when only one half of a pair is present, the other half is known. When DNA replicates, mistakes can occur. Most of these mistakes are cleaned up by proteins that double check the copy. However, if some mistakes get through and are replicated, then mutations occur. Multiple mutations in the same part of DNA can give rise to tumors. By U.S. National Library of Medicine [Public domain], via Wikimedia Commons.
Many agents affect development of breast cancer by causing mutations, or changes in the sequence of base nucleotides in the DNA, through deletions, replications or substitutions of original base pairs (Figure 1). These mutations, or changes in DNA sequence, are then replicated during regular cell-division processes. When the mutations occur in genes that regulate cell proliferation or aspects of tumor suppression, they can contribute to the development of cancer.
Data from the past several years has demonstrated another mechanism, in addition to classical gene mutations, by which alterations in genes can influence susceptibility to diseases including breast cancer (Firgure 2). This second mechanism, called “epigenetics,” refers to a change in the expression of a gene, rather than in the actual base combinations (Dworkin, 2009).
An example of epigenetic change occurs early in embryonic development when the cells of the body differentiate into various tissues such as eyes, breasts and blood vessels. Epigenetics guides the tissues of the body to become the different parts that make up a whole living thing by directing the synthesis of different proteins in different cells.
Normal epigenetic changes can be altered by exposures to environmental chemicals. The most common epigenetic changes are alterations in the rate of “methylation” of DNA or changes in DNA-associated histone proteins. In both cases, the result is a change in the rate (either activation or repression) of expression of an associated gene (Chiam, 2009). These epigenetic changes tend to be fairly small but are potentially cumulative over an individual’s lifetime (Baccarelli, 2009), and may therefore exert important effects on disease initiation.
Figure 2. The nucleotides in genes themselves don’t have to be changed to increase susceptibility to cancer. Instead, genes – which code for proteins in their “on” state – can be turned “off” or “on” by what are called epigenetic changes. Since the proteins that are created can alter how our bodies process information and nutrients, and maintain the right balance, these effects can profoundly affect health. Epigenetic changes can occur as a result to exposure to chemicals and radiation, and exposures in the womb or early childhood may affect health later in life. By U.S. National Library of Medicine [Public domain], via Wikimedia Commons.
One analogy is to liken genes—the DNA of a cell—to computer hardware and epigenetics to software, which tells the hardware what to do. So just as the same computer can produce letters or spreadsheets, depending on what software is being used, the same DNA in cells can, depending on the epigenetics, produce different proteins and structures. Thus cells with the same DNA can act as breast cells, stomach lining cells or light-sensing cells in the eye while having exactly the same DNA. Another way of thinking about it is that DNA is like a script for a play, and epigenetics determines how it is performed on stage.
DNA does not change throughout life, except in extreme cases involving mutation, but the epigenetic modifications that determine which genes are expressed and how they are expressed do change and are affected by a number of environmental factors, including diet, activity, stress and exposures. Research has now shown that some of these modifications can be passed down from generation to generation. Click here for a good video explanation of epigenetics.
A number of environmental toxicants, including heavy metals, several organic solvents and endocrine-disrupting compounds, have been shown to lead to epigenetic changes in gene activity. All of these substances are also implicated in an increased risk for breast cancer. Of particular importance, there is growing evidence from both human studies and, especially, animal studies that epigenetic changes very early in life can have profound effects on physical development and susceptibility to the onset of breast cancer much later (Chiam, 2009).
The evidence for epigenetic changes underlying non-inherited cancers, including breast cancers, has contributed to the emergence of a new model of the processes mediating cancer development (Soto 2004, 2008), referred to as Tissue Organization Field Theory (TOFT) of carcinogenesis. Rather than thinking about cancer development only as an accumulation of increasingly serious DNA mutations, TOFT builds on a more ecological view of cellular functioning and tissue organization. TOFT begins by recognizing that cell proliferation is the default state for cells, with processes and chemical signals critically regulating the rate of proliferation, and also that cells work in constant interaction with neighboring cells in the various tissues within an organ (Soto, 2004). Perturbations of the chemical signals or disruption of cell-to-cell interactions, potentially caused by environmental chemicals or radiation, may underlie the development of cancer in affected tissues.