Breast Cancer
Erin Wysong Hofstatter
Gina G. Chung
Lyndsay N. Harris
It has been said that cancer is a genetic disease and can be best understood by studying the DNA alterations that lead to the development of cancer. However, a deeper understanding of carcinogenesis requires insight into how these genetic changes alter cellular programs that lead to growth, invasion, and metastasis. This chapter is presented following the logical progression of DNA to RNA to protein, and it describes, at each step, the lesions that contribute to breast cancer carcinogenesis. The chapter also introduces new concepts in epigenetics, microRNAs, and gene expression analyses that illustrate how new biologic discoveries, and novel technologies, have profoundly affected our understanding of breast cancer pathogenesis within the past decade.
GENETICS OF BREAST CANCER
Breast cancer is a heterogeneous disease fundamentally caused by progressive accumulation of genetic aberrations, including point mutations, chromosomal amplifications, deletions, rearrangements, translocations, and duplications.1,2 Germline mutations account for only about 10% of all breast cancers, while the vast majority of breast cancers appear to occur sporadically and are attributed to somatic genetic alterations (Fig. 24.1).3
HEREDITARY BREAST CANCER
One of the most important risk factors for breast cancer is family history. Though familial forms comprise nearly 20% of all breast cancers, most of the genes responsible for familial breast cancer have yet to be identified. Breast cancer susceptibility genes can be categorized into three classes according to their frequency and level of risk they confer: rare high-penetrance genes, rare intermediate-penetrance genes, and common low-penetrance genes and loci4 (Table 24.1).
High-Penetrance, Low-Frequency Breast Cancer Predisposition Genes
BRCA1 and BRCA2
BRCA1 and BRCA2 mutations account for approximately half of all dominantly inherited hereditary breast cancers. These mutations confer a relative risk of breast cancer 10 to 30 times that of women in the general population, resulting in a nearly 85% lifetime risk of breast cancer development.5 BRCA1 and BRCA2 mutation carriers are quite rare among the general population, however, the prevalence is substantially higher in certain founder populations, most notably in the Ashkenazi Jewish population, where the carrier frequency is 1 in 40.
More than a thousand germline mutations have been identified in BRCA1 and BRCA2. Pathogenic mutations most often result in truncated protein products, although mutations that interfere with protein function also exist.4,5 Interestingly, penetrance of pathogenic BRCA1 and BRCA2 mutations and age of cancer onset appear to vary both within and among family members. Specific BRCA mutations as well as gene-gene and gene-environment interactions as potential modifiers of BRCA-related cancer risk are areas of active investigation.6,7
BRCA1-related breast cancers are characterized by features that distinguish them from both BRCA2-related and sporadic breast cancers.4 BRCA1-related tumors typically occur in younger women and have more aggressive features, with high histologic grade, high proliferative rate, aneuploidy, and absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2). This “triple-negative” phenotype of BRCA1-related breast cancers is further characterized by a “basal-like” gene expression profile of cytokeratins 5/6, 14, and 17, epidermal growth factor and P-cadherin.8
Though BRCA1 and BRCA2 genes encode large proteins with multiple functions, they primarily act as classic tumor suppressor genes that function to maintain genomic stability by facilitating double-strand DNA repair through homologous
recombination.8,9 When loss of heterozygosity (LOH) occurs via loss, mutation, or silencing of the wild type BRCA1 or BRCA2 allele, the resultant defective DNA repair leads to rapid acquisition of additional mutations, particularly during DNA replication, and ultimately sets the stage for cancer development.
recombination.8,9 When loss of heterozygosity (LOH) occurs via loss, mutation, or silencing of the wild type BRCA1 or BRCA2 allele, the resultant defective DNA repair leads to rapid acquisition of additional mutations, particularly during DNA replication, and ultimately sets the stage for cancer development.
 FIGURE 24.1 Genetic susceptibility to breast cancer. Familial breast cancer comprises approximately 20% to 30% of all breast cancers. BRCA1 and BRCA2 are two major high-penetrance genes associated with hereditary breast and ovarian cancer syndrome, which together account for nearly half of inherited breast cancers. Other rare breast cancer susceptibility genes have been identified, such as CHEK2,TP53, PTEN, and STK11. Several emerging low-penetrance genes and loci recently discovered by genomewide association studies account for a small proportion of familial breast cancers (<5%). To date, about half of familial breast cancers remain unexplained but are likely attributable to as yet unknown genes and/or polygenic susceptibility. (From Olopade O, et al. Advances in breast cancer: pathways to personalized medicine. Clin Cancer Res 2008;14(24): Fig 1.) |
The integral role of BRCA1 and BRCA2 in double-strand DNA repair holds potential as a therapeutic target for BRCA-related breast cancers. For example, platinum agents cause interstrand crosslinks, thereby blocking DNA replication and leading to stalled replication forks. Poly(adenosine diphosphate-ribose) polymerase-1 (PARP1) inhibitors additionally show promise as specific therapy for BRCA-related tumors. PARP1 is a cellular enzyme that functions in single-strand DNA repair through base excision and represents a major alternative DNA repair pathway in the cell.10,11 When PARP inhibition is applied to a background deficient in double-strand DNA repair, as is the case in BRCA-related tumor cells, the cells are left without adequate DNA repair mechanisms and ultimately undergo cell cycle arrest, chromosome instability, and cell death.4 Given their phenotypic similarities to BRCA1-related breast cancers, sporadic basal-like breast tumors may display sensitivity to PARP inhibition as well.11 Phase 2 studies are currently under way to explore the use of PARP inhibitors in both BRCA– and basallike, non-BRCA-related breast tumors.
Other High-Penetrance Genes
A small number of other high-risk, low frequency breast cancer susceptibility genes exist, and they include TP53, PTEN, STK11/LKB1, and CDH1.4,5,6 These high-penetrance genes confer an eight- to tenfold increase in risk of breast cancer as compared to noncarriers, but they collectively account for less than 1% of cases of breast cancer. Like BRCA1 and BRCA2, these genes are inherited in an autosomal dominant fashion and function as tumor suppressors.12 The hereditary cancer syndromes associated with each gene are usually characterized by multiple cancers in addition to breast cancer, as summarized in Table 24.1.
Moderate-Penetrance, Low Frequency Breast Cancer Predisposition Genes
Four genes have been identified that confer an elevated but moderate risk of developing breast cancer, namely CHEK2, ATM, BRIP1, and PALB2 (Table 24.1). Each of these genes confers approximately a two- to threefold relative risk of breast cancer in mutation carriers, though this risk may be higher in select clinical settings.5 Mutation frequencies in the general population are rare, on the order of 0.1% to 1%, though some founder mutations have been identified. Together, these genes account for approximately 2.3% of inherited breast cancer. The moderate relative risk of breast cancer of these genes in conjunction with the low population frequency renders this class of genes very difficult to detect with typical association studies. However, these genes were specifically selected for study as candidate breast cancer genes based on their known roles in signal transduction and DNA repair in close association with BRCA1 and BRCA2.6
TABLE 24.1 BREAST CANCER SUSCEPTIBILITY GENES AND LOCI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Low-Penetrance, High Frequency Breast Cancer Predisposition Genes and Loci
Both candidate gene and genome-wide association studies (GWAS) have identified a low-risk panel of approximately ten different alleles and loci in 15% to 40% of women with breast cancer5 (Table 24.1). Despite their frequency, the relative risk of breast cancer conferred by any one of these genetic variants alone is minimal, on the order of less than 1.5.4 Nevertheless, these alleles and loci may become clinically relevant in their suggestion of interactions with other high-, moderate-, and low-risk genes; these additive or multiplicative relationships could account for a measurable fraction of population risk. For example, association studies of FGFR2 and MAP3K1 within BRCA families showed that these single nucleotide polymorphisms (SNPs) conferred an increased risk in the presence of BRCA2 mutations.
Recent studies suggest that microRNA (miRNA) SNPs may also contribute to breast cancer susceptibility, and miRNAs appear to regulate many tumor suppressor genes (TSGs) and oncogenes via degradation of target mRNAs or repression of their translation. Thus, genetic variations in miRNA genes or miRNA binding sites could affect expression of TSGs or oncogenes and, thereby, cancer risk. For example, specific SNPs located within pre-miR-27a and miR-196a-2 genes have been associated with reduced breast cancer risk.13
SOMATIC CHANGES IN BREAST CANCER
The vast majority of breast cancers are sporadic in origin, ultimately caused by accumulation of numerous somatic genetic alterations.1 Recent data suggest that a typical individual breast cancer harbors anywhere from 50 to 80 different somatic mutations.2 Many of these mutations occur as a result of erroneous DNA replication; others may occur through exposure to exogenous and endogenous mutagens. To date, hundreds of candidate somatic breast cancer genes have been identified through GWAS.14,15 Yet the full range of somatic mutations will not be clear until hundreds more breast tumor samples are sequenced. To this end, international efforts are currently underway to produce a comprehensive catalog of these genetic alterations.
Determining the role of each identified mutation in the development of breast cancer remains a substantial challenge. Data suggest that the vast majority of identified somatic DNA mutations in a given tumor are “passenger” mutations, representing harmless, biologically neutral changes that do not contribute to oncogenesis.1,2 Conversely, “driver” mutations confer a growth advantage on the cell in which they occur and appear to be implicated in cancer development. By definition, driver mutations are found in candidate cancer genes (CAN).15
Although the catalog of somatic mutations and CAN genes is still incomplete, it is comprehensive enough that various structural features are starting to emerge. When specific driver mutations are cataloged among several different breast tumors, a bimodal cancer “genomic landscape” appears, comprising a small number of commonly mutated gene “mountains” among hundreds of infrequently mutated gene “hills.”1,2 Gene mountains correspond to the most frequently mutated genes found within breast tumors, such as TP53, CDH1, phosphatidylinositol 3-kinase (PI3K), cyclin D, PTEN, and AKT.6 Each individual gene hill, on the other hand, is typically found in less than 5% of breast tumors.1,16
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