Appendix E

Glossary

Absolute risk: Risk of developing a disease over a set time period. Similar in concept to the incidence rate, calculated by dividing the number of new cases of a given disease by the number of people at risk for the disease over a defined period of time.

Adaptive immunity: A second line of defense, distinct from the more generalized innate immune response, in which the body reacts in a manner specific to invading pathogens and any toxic molecules they produce. Adaptive immune responses often confer long-lasting protection from a specific pathogen (adapted from Alberts et al., 2002).

Adipose tissue: Specialized connective tissue composed of adipocytes, or fat cells.

Allele: One of two or more versions of a gene. An individual inherits two alleles for each gene, one from each parent. If the two alleles are the same, the individual is homozygous for that gene; if the two alleles are different, the individual is said to be heterozygous (NHGRI, 2011).

Androgen: A sex hormone responsible for the development and maintenance of male sex characteristics.

Apoptosis: A complex program of cellular self-destruction and death (adapted from Weinberg, 2007).

Aromatase: An enzyme that catalyzes the conversion of testosterone to estradiol.

Association: Statistical relationship between two or more events, characteristics, or other variables (CDC, 2010).

Attributable risk: The percentage of cases that occur in the exposed group that is in excess of the cases in the comparison group.



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Appendix E Glossary Absolute risk: Risk of developing a disease over a set time period. Similar in concept to the incidence rate, calculated by dividing the number of new cases of a given disease by the number of people at risk for the disease over a defined period of time. Adaptive immunity: A second line of defense, distinct from the more gen- eralized innate immune response, in which the body reacts in a manner specific to invading pathogens and any toxic molecules they produce. Adaptive immune responses often confer long-lasting protection from a specific pathogen (adapted from Alberts et al., 2002). Adipose tissue: Specialized connective tissue composed of adipocytes, or fat cells. Allele: One of two or more versions of a gene. An individual inherits two alleles for each gene, one from each parent. If the two alleles are the same, the individual is homozygous for that gene; if the two alleles are different, the individual is said to be heterozygous (NHGRI, 2011). Androgen: A sex hormone responsible for the development and mainte- nance of male sex characteristics. Apoptosis: A complex program of cellular self-destruction and death (adapted from Weinberg, 2007). Aromatase: An enzyme that catalyzes the conversion of testosterone to estradiol. Association: Statistical relationship between two or more events, character- istics, or other variables (CDC, 2010). Attributable risk: The percentage of cases that occur in the exposed group that is in excess of the cases in the comparison group. 399

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400 BREAST CANCER AND THE ENVIRONMENT Benign: Describing a growth that is confined to a specific site within a tis- sue and gives no evidence of invading adjacent tissue (Weinberg, 2007). Benign tumors are typically not life threatening. Biomarker: A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to an intervention (IOM, 2010). Body mass index (BMI): A measure of adiposity calculated from an indi- vidual’s height and weight as an alternative for direct measures of body fat (CDC, 2011). BRCA1/BRCA2: Human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to heredi- tary breast and ovarian cancers (NCI, 2011). Carcinogen: An agent that contributes to the formation of a tumor (Weinberg, 2007). Case–control study: A type of observational analytic study. Enrollment into the study is based on presence (“case”) or absence (“control”) of disease. Characteristics such as previous exposure are then compared between cases and controls (CDC, 2010). Chromatin: Complex of DNA, histones, and non-histone proteins found in the nucleus of a eukaryotic cell. The material of which chromosomes are made (Alberts et al., 2002). Circadian rhythm: Physical, mental and behavioral changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment (NIGMS, 2011). Cluster: An aggregation of cases of a disease or other health-related condi- tion, particularly cancer and birth defects, which are closely grouped in time and place. The number of cases may or may not exceed the expected number; frequently the expected number is not known (CDC, 2010). Cohort: A well-defined group of people who are followed up for the inci- dence of new diseases or events, as in a cohort or prospective study. A group of people born during a particular period or year is called a birth cohort (CDC, 2010). Confidence interval: A range of values for a statistic of interest, such as a rate, constructed so that this range has a specified probability of includ- ing the true value of the variable. The specified probability is called the confidence level, and the endpoints of the confidence interval are called the confidence limits (CDC, 2010). It may be thought of as the range of values that are consistent at a given level of confidence with a quantitative observation or measurement. Confidence limit: The minimum or maximum value of a confidence interval (CDC, 2010).

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401 APPENDIX E Confounding factor: A variable or characteristic that is causally related to the outcome of interest, and that is also related to the exposure, but is not a consequence of the exposure. Control: In a case–control study, comparison group of persons without disease (CDC, 2010). Correlation: Indicative of a relationship between two measurements. Cytochrome p450 (CYP) enzyme system: A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spec- trum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed-function oxygenases). In animals, these CYP enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (bio- transformation) (National Library of Medicine, 2011). DMBA: 7,12-Dimethylbenz[a]anthracene, a polycyclic aromatic hydro- carbon that is a potent carcinogen often used as a tumor initiator in laboratory studies. DNA: Deoxyribonucleic acid or the double-stranded helix of nucleotides carrying the genetic information of the cell. Encodes information for proteins and is able to self-replicate. DNA adduct: Covalent adducts between chemical mutagens and DNA. Such couplings activate DNA repair processes and, unless repaired prior to DNA replication, may lead to nucleotide substitutions, dele- tions, and chromosome rearrangements (Rieger et al., 2007). DNA methylation: Addition of a methyl group to DNA. Extensive methyla- tion of the cytosine base in CG sequences is used in vertebrates to keep genes in an inactive state; one mechanism for “epigenetic” regulation of gene expression. Ductal carcinoma in situ (DCIS): A noninvasive breast lesion in which abnormal cells multiply and form a growth within the milk duct of the breast. Some of these lesions can progress to become invasive cancers, but the risk of progression is poorly quantified. Ecological fallacy: The thinking that relationships observed for groups necessarily hold for individuals (Freedman, 1999). Endocrine: Referring to a gland that secretes fluids into the general circula- tion, or the signal pathway of a hormone or factor. Endocrine disrupting compound (EDC): An exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of the natural hormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processes (EPA, 2011).

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402 BREAST CANCER AND THE ENVIRONMENT Endogenous: Developing or originating within; produced normally by the body. Environment: Factors not directly heritable through DNA. Epigenetics: An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA se- quence (Berger et al., 2009) Epigenome: A set of changes to the genome passed down from one genera- tion to the next that does not include alterations in genetic material. Epoxide: An organic compound containing a three-membered ring of an oxygen atom and two carbon atoms. Estrogen: Female reproductive hormone produced by the ovaries. Estrogen response element (ERE): Recognition site in the regulatory portion of a gene to which the estrogen receptor binds when complexed with a “ligand” (estrogen or estrogen-like chemicals). Etiology: Cause or origin (of a disease). Exogenous: Originating from external factors; not produced internally by the body. Extracellular matrix: A component of tissues largely filled by an intricate network of macromolecules and composed of a variety of proteins and polysaccharides that are secreted locally and assembled into an orga- nized meshwork in close association with the surface of the cell that produced them (Alberts et al., 2002). G protein coupled receptor (GPCR): A 7 transmembrane domain recep- tor that activates a protein upon ligand binding, resulting in a second messenger-initiated pathway involving a series of intracellular events. Genome: The totality of genetic information belonging to a cell or an or- ganism; in particular, the DNA that carries this information (Alberts et al., 2002). Hazard: Potential to cause harm; differs from risk. Heritable: Able to be passed from one generation to the next. High-risk group: A group in the community with an elevated risk of disease (CDC, 2010). Histone: One of a group of small abundant proteins, rich in arginine and lysine, four of which form the nucleosome on the DNA in eukaryotic chromosomes (Alberts et al., 2002). Immunosurveillance: A process in which the immune system of a host rec- ognizes antigens of newly arising tumors and eliminates these tumors before they become clinically evident (adapted from Ochsenbein, 2002). in situ: Occurring at the site of origin (Weinberg, 2007).

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403 APPENDIX E in utero: Occurring in the uterus during embryonic or fetal development (Weinberg, 2007). in vitro: Occurring in tissue culture, in cell lysates, or in purified reaction systems in the test tube (Weinberg, 2007). in vivo: Occurring in a living organism (Weinberg, 2007). Incidence rate: A measure of the frequency with which an event, such as a new case of illness, occurs in a population over a period of time. The denominator is the population at risk; the numerator is the number of new cases occurring during a given time period (CDC, 2010). For ex- ample, an incidence rate of ovarian cancer is only calculated in women, and the incidence of prostate cancer is only calculated in men. Lactation: Period following birth in which milk is secreted. Latency: Elapsed time between exposure and response. Malignant: Describing a growth that shows evidence of being locally in- vasive and possibly even metastatic; malignant tumors are generally considered life threatening. Mammary gland: The milk-producing glands of female mammals. Melatonin: A hormone secreted by the pineal gland, which helps regulate other hormones and maintain the body’s circadian rhythm. Menarche: First occurrence of menstruation in a woman. Menopause: The point at which menstruation ceases in a woman’s life. Messenger RNA: See mRNA. Meta-analysis: Statistical technique for combining the findings from inde- pendent studies (Crombie and Davies, 2009). Metastasis: The spread of cancer from its site of origin to another part of the body. Methylation: See DNA methylation. Mitosis: The process by which a single cell separates its complement of chromosomes into two equal sets in preparation for the division into two daughter cells (Weinberg, 2007). Morbidity: Any departure, subjective or objective, from a state of physi- ological or psychological well-being (CDC, 2010). Mortality rate: A measure of the frequency of occurrence of death in a defined population during a specified interval of time (CDC, 2010). mRNA: RNA sequences that serve as templates for protein synthesis (Reiger et al., 2007). Multistage carcinogenesis: A conceptual division of carcinogenesis into four steps: tumor initiation, tumor promotion, malignant conversion, and tumor progression (Alberts et al., 2002). Mutagen: An agent that induces a mutation.

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404 BREAST CANCER AND THE ENVIRONMENT Mutagenesis: The process by which a change in nucleotide sequence, or mutation, occurs. Mutation: Heritable change in the nucleotide sequence of a chromosome (Alberts et al., 2002). Neoplasm: An abnormal new tumor mass. Neoplasms may be benign or malignant. Observational study: Epidemiologic study in situations where nature is al- lowed to take its course. Changes or differences in one characteristic are studied in relation to changes or differences in others, without the intervention of the investigator (CDC, 2010). Odds ratio: A measure of association that quantifies the relationship be- tween an exposure and health outcome from a comparative study. For low-frequency outcomes, such as cancer, the odds ratio generally pro- vides a good estimate of relative risk (see Relative risk) (CDC, 2010). Oncogene: A cancer-inducing gene (Weinberg, 2007). p53: Tumor suppressor gene found mutated in about half of human can- cers. It encodes a gene regulatory protein that is activated by damage to DNA and is involved in blocking further progression through the cell cycle (Alberts et al., 2002). Paracrine: Referring to the signaling path of a hormone or factor that is released by one cell and acts on a nearby cell (Weinberg, 2007). Parity: The status of having given birth (parous), or not (nulliparous); the number of children a woman has borne (Weinberg, 2007). Phytoestrogen: A chemical produced by plants that can mimic the hormone estrogen (Sprecher Institute for Comparative Research, 2001). Polymorphism: Genetic polymorphism (literally means “many forms”) is defined as the occurrence of two or more relatively common normal alleles for a single locus. The difference between a polymorphism and a mutation is that a polymorphism occurs commonly and it is associated with a normal phenotype (Kufe et al., 2003). Population: The total number of inhabitants of a given area or country. In sampling, the population may refer to the units from which the sample is drawn, not necessarily the total population of people (CDC, 2010). Population attributable risk (PAR): Population-based measure of the per- centage of excess cases associated with the exposure of interest (assum- ing that the relationship between the exposure and the disease outcome is causal) that also takes into account the distribution of that exposure within the population. Prevalence: The number or proportion of cases or events or conditions in a given population at a given time (CDC, 2010).

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405 APPENDIX E Prospective cohort study: A type of observational study that follows over a period of time a group of individuals, or cohort, who differ with respect to certain factors under study, in order to determine how these factors affect rates of an outcome. Randomized controlled trial: A study that randomly assigns individuals to an intervention group or to a control group, in order to measure the effects of the intervention (U.S. Department of Education, 2004). When practical and ethical, this study design provides the most direct evidence of a causal association between an exposure and an outcome. Reactive oxygen species: Molecules and ions of oxygen that have an un- paired electron, thus rendering them extremely reactive. Superoxide anion and hydroxyl radicals are the most common examples. Receptor: A protein that is capable of specifically binding a signal molecule. Relative risk: A ratio of the absolute risk (incidence) of disease in an ex- posed group (or groups with different levels of exposure) to the abso- lute risk (incidence) of disease in an unexposed group (or some other designated comparison group). Risk: The probability that an event will occur or the likelihood of harm, for example, that an individual will become ill or die within a stated period of time or by a certain age (CDC, 2010). RNA: Ribonucleic acid produced through DNA transcription, exists in ribosomal (rRNA), messenger (mRNA), and transfer (tRNA) forms, and provides the template for protein translation. Statistical power: Power of a statistical test is the probability that the test will reject the null hypothesis when the alternative hypothesis is true. Stem cell: Cell type within a tissue that is capable of self-renewal and is also capable of generating daughter cells that develop new phenotypes, including those that are more differentiated than the phenotype of the cell (Weinberg, 2007). Stroma: The mesenchymal components of the epithelial and hematopoetic tissues and tumors, which may include fibroblasts, adipocytes, endothe- lial cells, and various immunocytes as well as associated extracellular matrix (Weinberg, 2007). Target cell: A cell that is acted on by an outside agent; a particular cell type that is specifically or uniquely altered by a xenobiotic, hormone, or other stimulus that is external to the cell. Thelarche: Onset of breast development in prepubertal girls. Toxicology: The study of the adverse effects of chemical or physical agents on living organisms (Klaassen, 2001).

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406 BREAST CANCER AND THE ENVIRONMENT Transcription factor: Protein that binds to specific DNA sequences, facilitat- ing the transfer of information from DNA to RNA. Tumor: An abnormal growth of body tissue. Tumor suppressor gene: A gene whose partial or complete inactivation, oc- curring in either the germ line or the genome of a somatic cell, leads to an increased likelihood of cancer progression (Weinberg, 2007). Validity: The degree to which a measurement actually measures or detects what it is supposed to measure (CDC, 2010). Variable: Any characteristic or attribute that can be measured (CDC, 2010). Variance: A measure of the dispersion shown by a set of observations, de- fined by the sum of the squares of deviations from the mean, divided by the number of degrees of freedom in the set of observations (CDC, 2010). Xenoestrogens: Compounds that mimic estrogens, although they may differ chemically from the forms of estrogen produced normally in the body. REFERENCES Alberts, B., A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter. 2002. Molecular biol- ogy of the cell, 4th ed. New York: Garland Science. http://www.ncbi.nlm.nih.gov/books/ NBK21070 (accessed November 18, 2011). Berger, S. L., T. Kouzarides, R. Shiekhattar, and A. Shilatifard. 2009. An operational definition of epigenetics. Genes Dev 23(7):781–783. CDC (Centers for Disease Control and Prevention). 2010. Epi glossary. http://www.cdc.gov/ reproductivehealth/Data_Stats/Glossary.htm (accessed December 21, 2011). CDC. 2011. About BMI for adults. http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/ index.html (accessed November 18, 2011). Crombie, I. K., and H. T. O. Davies. 2009. What is meta-analysis? http://www.whatisseries. co.uk/whatis/ (accessed November 18, 2011). EPA (Environmental Protection Agency). 2011. Endocrine disruptors research. http://www. epa.gov/ncer/science/endocrine/index.html (accessed November 18, 2011). Freedman, D. A. 1999. Ecological inference and the ecological fallacy. http://www.stanford. edu/class/ed260/freedman549.pdf (accessed November 18, 2011). IOM (Institute of Medicine). 2010. Evaluation of biomarkers and surrogate endpoints in chronic disease. Washington, DC: The National Academies Press. Klaassen, C. D., ed. 2001. Casarett and Doull’s Toxicology: The basic science of poisons, 6th ed. New York: McGraw Hill. Kufe, D. W., R. E. Pollock, R. R. Weichselbaum, R. C. Bast, T. S. Gansler, J. F. Holland, and E. Frei (eds). 2003. Holland-Frei cancer medicine, 6th ed. Hamilton, Ontario, Canada: BC Decker. http://www.ncbi.nlm.nih.gov/books/NBK12354/ (accessed November 18, 2011). National Library of Medicine. 2011. Genetics home reference: Your guide to understanding genetic conditions. http://ghr.nlm.nih.gov/glossary=cytochromep450 (accessed November 18, 2011). NCI (National Cancer Institute). 2011. http://www.cancer.gov (accessed November 18, 2011).

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407 APPENDIX E NHGRI (National Human Genome Research Institute). 2011. Talking glossary of genetic terms. http://www.genome.gov/glossary/?id=4 (accessed November 18, 2011). NIGMS (National Institute of General Medical Sciences). 2011. Circadian rhythms fact sheet. http://www.nigms.nih.gov/Education/Factsheet_CircadianRhythms.htm (accessed November 18, 2011). Ochsenbein, A. F. 2002. Principles of tumor immunosurveillance and implications for immu- notherapy. Cancer Gene Ther 9(12):1043–1055. Rieger, R., A. Michaelis, and M. M. Green. 1991. Glossary of genetics: Classical and molecu- lar, 5th ed. New York: Springer-Verlag. http://www.reference.md/files/D018/mD018736. html (accessed November 18, 2011). Sprecher Institute for Comparative Research. 2001. Phytoestrogens and breast cancer. http:// envirocancer.cornell.edu/factsheet/diet/fs1.phyto.cfm (accessed November 18, 2011). U.S. Department of Education. 2004. Identifying and implementing educational practices sup- ported by rigorous evidence: A user friendly guide. http://www2.ed.gov/rschstat/research/ pubs/rigorousevid/guide_pg5.html (accessed November 18, 2011). Weinberg, R. A. 2007. The biology of cancer. New York: Garland Science.

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