devita, principios de practica oncologica 8va edicion

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Editors: DeVita, Vincent T.; Lawrence, Theodore S.; Rosenberg, Steven A.Title: Devita, Hellman & Rosenberg's Cancer: Principles & Practice of Oncology, 8th EditionCopyright 2008 Lippincott Williams & Wilkins> Table of Contents > Volume Two > Part 3 - Practice of Oncology > Chapter 43 - Cancer of the BreastChapter 43Cancer of the BreastSection 1: The Molecular Biology of Breast CancerSuzanne D. ConzenTatyana A. GrushkoOlufunmilayo I. OlopadeThe past 20 years have witnessed a dramatic increase in our understanding of multistep carcinogenesis and the central role of genetic alterations in the diagnosis, treatment, and prevention of breast cancer. Advances in DNA microarray technology and other methods of large-scale gene expression analysis have been adopted for both biological characterization and more recently, for therapeutic decision making in breast cancer treatment. Increasing our understanding of the molecular biology and gene expression signatures of breast cancer continues to improve prevention, detection, and treatment strategies for breast cancer patients. For example, the discovery of a physiological role for the estrogen receptor (ER) in breast cancer by Nobel Prize winner Charles Huggins, paved the way for antiestrogen therapy. Similarly, amplification of the HER2 oncogene has proven to be the major determinant of sensitivity to treatment with the anti-HER2 humanized monoclonal antibody, trastuzumab. Thus, targeting specific signaling pathways in breast cancer treatment has proven value.Although many molecular abnormalities relating to growth factor signaling in breast cancers have been recently described, the specific genes causing more than half of inherited breast cancers remain largely unknown (Fig. 43.1.1). Interestingly, most of the known the genes implicated in inherited breast cancer are involved in DNA repair pathways. For example, deleterious mutations in the BRCA1 and BRCA2 account for most inherited breast cancer; they are implicated in about 40% of all familial breast cancers. In this chapter, both acquired and inherited determinants of breast cancer are reviewed, with the goal of placing molecular biology in a clinically relevant context.Genetics of Breast CancerGenetic PredispositionBreast cancer is an extremely heterogeneous disease caused by interactions of both inherited and environmental risk factors that lead to progressive accumulation of genetic and epigenetic changes in breast cancer cells. Although epidemiological evidence supports the existence of certain risk factors (e.g., age, obesity, alcohol intake, lifetime estrogen exposure, and mammographic density), a family history of breast cancer remains the strongest risk factor for the disease. Familial forms comprise approximately 20% of all breast cancers and appear to have a distinctive pathogenesis dependent on the particular susceptibility gene involved (Fig. 43.1.1).1,2Although the genes responsible for most familial breast cancers have yet to be identified, approximately half of familial cancers are caused by germline mutations in tumor suppressor genes (TSGs), most of which have functions implicated in preserving genome fidelity. These genes include (1) BRCA1 and BRCA2, (2) other TSGs that are associated with rare familial cancer syndromes such as p53, PTEN, and ATM, and (3) additional low- to moderate-risk genes such as CHEK2, BRIP1, PALB2, NBS1, RAD50, and the mismatch repair genes MSH2 and MLH.3 Recently, genome-wide association studies that examine genetic variation (single nucleotide polymorphisms) in the context of familial breast cancer and case control studies of breast cancer have uncovered common low penetrance genetic variations in at least 120 candidate genes. Interestingly, among these candidate genes, the main contributors to an association with breast cancer risk are genes involved in cell cycle control, steroid hormone metabolism, and cell signaling pathways. Common susceptibility alleles of CASP8, TGFB1, FGFR2, TNC9, MAP3K1, and LSP1 have repeatedly shown the strongest and most consistent evidence for an association with breast cancer.4,5,6,7 A summary of known and emerging genes associated with breast cancer susceptibility is provided in Table 43.1.1.BRCA1 and BRCA2BRCA1 and BRCA2 are located on chromosomes 17q12-21 and 13q12-13, respectively, and are considered classic TSGs because P.1596

one inherited defective copy of the gene is sufficient for cancer predisposition, but the loss of the wild-type allele is required for tumorigenesis.8

Figure 43.1.1. Genetics of breast cancer. The majority of breast cancers are sporadic, occur randomly, and carry somatic genetic alterations. Hereditary cancer occurs in multiple family members due to germline mutations in high-risk genes which are inherited in autosomal dominant pattern. BRCA1 and BRCA2 are two major high-risk genes associated with hereditary breast cancer. Mutations in CHEK2 contribute to a substantial fraction of familial breast cancer. Carriers of TP53 mutations develop Li-Fraumeni syndrome and are at high risk of developing early onset breast cancer, but these mutations are very rare. Susceptibility alleles in other genes, such as PTEN, ATM, STK11/LKB1, and MSH2/MLH1 are also very rare causes of breast cancer. The majority of familial clustering of breast cancer is unexplained. The susceptibility to breast cancer in this group is presumed to be due to either additional high-penetrance susceptibility genes (which remain to be identified) or variants at many low-penetrance loci, each conferring a moderate risk of the disease (polygenic susceptibility).

BRCA1 and BRCA2 encode large multifunctional proteins with multiple sites of proteinprotein interactions. BRCA1 has three major functional domains but has also been found in multiple protein complexes. In fact, it remains unclear which of the many functions contribute to its specific role as a major breast and ovarian cancer susceptibility gene. First, an amino-terminal RING finger domain forms heterodimers with the BRCA1-associated ring domain 1 (BARD1) protein. This association results in BRCA1 possessing E3 ubiquitin ligase activity. Recent data relate ubiquitin modification of BRCA1 to DNA damage response and to the control of centrosome dynamics.9 A second important region contains two nuclear localization signals and a binding region for P53, MYC, Rb, as well as the zinc-finger and BRCA1-interacting protein with a CRAB domain 1 (ZBRK1), which cooperates with BRCA1 to repress transcription. Third, a large region located in the C-terminal half of the protein is required for cell cycle control, chromatin modification, and DNA-repair-related functions. The DNA-binding domain in the central part of this region forms the BRCA1-associated surveillance complex with a number of proteins including MSH2-MSH6, MRE11-RAD50-NBS1, BLM, MDC1, ATM, ATR, CDK2, CHK2, and RAD51. SQ-cluster domains are sites phosphorylated by ATM/ATR. A pair of BRCA1 C-terminal (BRCT) domains possess phosphopeptide binding motifs with a high affinity for phosphoserine and phosphothreonine residues. BRCT domains are found in many proteins involved in the DNA repair pathway. BRCT domains of BRCA1 bind to the histone deacetylase (HDAC) complex, chromatin remodeling factors SWI/SNF, RNA polymerase II, p300, BACH1, CtIP, and BRCA2 and contain second-binding sites for P53 and Rb. Interaction of BRCT repeats of BRCA1 with CHK1 and Polo-like kinase (PLK1) regulates the G2/M and G1/S checkpoints and control apoptosis. In summary, it is apparent that in complex with other proteins, BRCA1 contributes to many cellular processes including homologous recombination, DNA damage response, cell cycle checkpoint control, ubiquitination, transcriptional regulation, chromatin modification, centrosome duplication, and X-chromosome inactivation.10,11,12,13,14Although BRCA2 also contains two nuclear localization signals, the presence of RAD51-binding motifs within eight central BRC repeats supports the hypothesis that BRCA2 plays a role in double-strand break repair and both mitotic and meiotic recombination. The C-terminal DNA-binding domain of BRCA2 is a region that binds to both single-stranded DNA and to a DSS1 protein. This region contains an additional RAD51-binding motif that is distinct from the BRC repeats and regulated by CDK-dependent phosphorylation. This complex formation is important for properly controlled recombination and centrosome duplication. Although there is no sequence similarity, BRCA1 and BRCA2 are functionally related. Functions so far ascribed to BRCA2 are DNA recombination and homologous repair, transcription, chromatin remodeling, centrosome duplication, and cytokinesis. Both BRCAs are in the class of so-called caretaker genes, which through the multiple functions discussed above use a variety of pathways to ensure genomic stability.8,10,11P.1597


Table 43.1.1 Breast Cancer Susceptibility Genes

GeneAbbreviationLocationProtein FunctionAssociated Syndrome, Cancer PredispositionBreast Cancer Risk Range

BRCA1ADBReast CAncer gene 117q12-21DNA repair, transactivationRHereditary breast/ovarian cancer Bilateral/multifocal breast tumor; risk of prostate colon, liver, and bone cancer60%85% (lifetime); 15%40% risk of ovarian cancer

BRCA2ADBReast CAncer gene 213q12-13DNA repair, transactivationRHereditary breast/ovarian cancer D1 Fanconi Anemia (caused by biallelic mutations) Male breast cancer; risk of pancreas, gall bladder, pharynx, stomach, melanoma, and prostate cancer37%84% (by age 70), 60%85% (lifetime), 15%40% risk of ovarian cancer

TP53ADTumor Protein 5317p13.1Cell cycle regulation, DNA repair, apoptosisLi-Fraumeni syndromeRBreast cancer, soft tissue sarcoma, CNS-tumors, adrenocortical cancer, leukemia, prostate cancer risk50%89% (by age 50), 90% in Li-Fraumeni syndrome survivors