ReviewField cancerization in mammary carcinogenesis — Implications for prevention and treatment of breast cancer
Section snippets
Cancer is a multistep molecular and cellular process
The development of a clinical cancer occurs over a long period of time and requires multiple molecular alterations and evolution of cellular populations with increasingly aggressive phenotypic characteristics. While the time required for completion of the process of carcinogenesis is not well established for any form of human cancer, estimates suggest that this process unfolds over decades. It follows that most cancers are diseases of old (or older) age, although there are exceptions (pediatric
Molecular and cellular heterogeneity of cancer
A lasting paradigm of cancer biology is that cancer is a disease of clonal growth. Hence, the multicellular disease that is cancer originates in a single cell. This concept has been variously described in simplistic terms. Fig. 1 depicts the clonal evolution of cancer — beginning with a normal epithelial cell and ending with a clinical metastatic cancer. This conceptual depiction emphasizes the multiple steps that occur during carcinogenesis, with multiple molecular alterations and multiple
Field cancerization
Field cancerization was first proposed to account for the multiple cancers that develop in cigarette smokers within the carcinogen-exposed field that comprises the aerodigestive tract (Slaughter et al., 1953). Since the first description of field cancerization, this concept has been applied to cancers in many different tissues (Chai and Brown, 2009). The idea of field cancerization fits very well for carcinogen-exposed tissue fields (like cigarette smoke-exposed respiratory epithelium or
Natural history and molecular classification of breast cancer
Breast cancer is a heterogeneous disease characterized by variant pathological features, disparate response to therapeutics, and substantial differences in long-term patient survival. DNA microarray-based transcription profiling of invasive breast cancer identified distinct and reproducible molecular subtypes that are associated with different clinical outcomes (Perou et al., 2000, Sorlie et al., 2001, Sorlie et al., 2003, Sotiriou et al., 2002, Sotiriou et al., 2003, van de Vijver et al., 2002
Molecular alterations in breast cancer
The development of breast cancer occurs in response to an accumulation of genetic and epigenetic abnormalities that drive uncontrolled growth of breast epithelial cells. The primary manifestation of the genetic and epigenetic abnormalities occurring in breast cancer are reflected in the cellular behaviors observed in cancer cells (autonomy of growth control, resistance to growth suppression and apoptosis, ability to invade local and metastasize to distant sites) and the underlying gene
Epigenetic alterations in breast cancer
Neoplastic transformation is associated with alterations in DNA methylation, including both global hypomethylation and gene-specific hypermethylation (Baylin, 2001, Baylin et al., 1998, Herman and Baylin, 2003). Hypomethylation of cancer cell genomes is associated with loss of methylation in CpG-depleted regions where most CpG dinucleotides would be expected to be methylated (Feinberg and Vogelstein, 1983a, Feinberg and Vogelstein, 1987, Goelz et al., 1985). The loss of methylation in these
Field cancerization in breast cancer
Numerous lines of evidence suggest that breast cancers may develop through field cancerization, including significant observations made in patients with early (pre-invasive) breast neoplasms (DCIS). Molecular evidence for field cancerization in the breast includes the observation of both genetic and epigenetic alterations in otherwise normal appearing breast epithelium. Genomic instability in the form of allelic imbalances have been characterized in histologically normal breast tissue adjacent
Field cancerization in early breast cancer — implications for treatment
DCIS is typically treated with surgery (either lumpectomy or mastectomy) and local radiation treatment (for patients undergoing breast conserving surgery). Patients undergoing local excision and radiation therapy have a higher risk for local recurrence (12% of these patients develop recurrent disease) than patients who choose mastectomy (1% of these patients develop recurrent disease) (Allegra et al., 2010). Currently, > 500,000 women are alive that have a prior diagnosis of DCIS (Allegra et
Perspective
Given the prevalence of DCIS (pure DCIS or DCIS associated with invasive breast cancer), expansion and improvement of our understanding of the molecular pathogenesis of this disease is essential to the development of new strategies for effective prevention of breast cancer and improved treatment of patients with pre-invasive or invasive breast neoplasms. With development of a greater understanding of the required molecular alterations that drive breast cancer, biomarkers for premalignant stages
Conflict of Interest statement
The authors declare no conflicts of interest.
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