Review
Field cancerization in mammary carcinogenesis — Implications for prevention and treatment of breast cancer

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Abstract

The natural history of breast cancer unfolds with the development of ductal carcinoma in situ (DCIS) in normal breast tissue, and evolution of this pre-invasive neoplasm into invasive cancer. The mechanisms that drive these processes are poorly understood, but evidence from the literature suggests that mammary carcinogenesis may occur through the process of field cancerization. Clinical observations are consistent with the idea that (i) DCIS may arise in a field of altered breast epithelium, (ii) narrow surgical margins do not remove the entire altered field (contributing to recurrence and/or disease progression), and (iii) whole-breast radiation therapy is effective in elimination of the residual field of altered cells adjacent to the resected DCIS. Molecular studies suggest that the field of altered breast epithelial cells may carry cancer-promoting genetic mutations (or other molecular alterations) or cancer promoting epimutations (oncogenic alterations in the epigenome). In fact, most breast cancers develop through a succession of molecular events involving both genetic mutations and epimutations. Hence, in hereditary forms of breast cancer, the altered field reflects the entire breast tissue which is composed of cells with a predisposing molecular lesion (such as a BRCA1 mutation). In the example of a BRCA1-mutant patient, it is evident that local resection of a DCIS lesion or localized but invasive cancer will not result in elimination of the altered field. In sporadic breast cancer patients, the mechanistic basis for the altered field may not be so easily recognized. Nonetheless, identification of the nature of field cancerization in a given patient may guide clinical intervention. Thus, patients with DCIS that develops in response to an epigenetic lesion (such as a hypermethylation defect affecting the expression of tumor suppressor genes) might be treated with epigenetic therapy to normalize the altered field and reduce the risk of secondary occurrence of DCIS or progression to invasive 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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