CpG Island Hypermethylation in Breast Cancer Progression and Metastasis

Abstract

Breast cancer is the most common malignancy in women and comprises 18% of all female cancers. The incidence of breast cancer increases with age and in the western countries the disease is the single most common cause of death among women aged 40–50, accounting for about a fifth of all deaths in this age group. The advent of mammography screening has led to an increased detection of pre-invasive mammary lesions and a better elucidation of the pathological events that precede the development of invasive breast carcinoma. Invasive breast cancer is classified in two main morphological subtypes ductal carcinoma representing about 80% of breast malignancy, and lobular carcinoma that accounts for approximately 10% of breast cancers. Among pre-invasive breast lesions, the hyperplasia of the usual type (HUT) is morphologically and phenotypically heterogeneous, whereas atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are homogenous in cell type and marker expression. On the basis of epidemiological and clinical data ADH at the present is seen as a risk factor and not as a direct precursor of DCIS or invasive lesions. Thus the only proliferative lesion that can be considered as a true precursor of invasive breast cancer is DCIS. This model of pathological progression is partially corroborated by genetic studies. In recent years progresses were made in defining some of the critical processes involved in breast cancer development and progression, and CpG island hypermethylation is emerging as one of the main mechanisms for inactivation of cancer related genes in breast tumorigenesis. Three types of genes are involved in carcinogenesis: oncogenes, tumor suppressor genes (TSGs) and stability (caretaker) genes. They encode for proteins involved in a series of pathways that control the basic functions of the cell: proliferation, communication with neighboring cells and with extra cellular matrix, senescence and programmed cell death (apoptosis). Epigenetic mechanism can modulate these pathways by acting directly on tumor suppressor genes and stability genes and indirectly on oncogenes through their regulators. Studies on several tumor types indicate changes in the number of methylated genes as well as an increase in methylation density during tumor progression, but only few studies have investigated changes in promoter hypermethylation during breast cancer progression. This is mainly due to the intrinsic difficulties to collect lesions that might be representative of all stages of the diseases. An increase in promoter hypermethylation was demonstrated for CCND2, ESR1, CDH1, RASSF1A, AP2α, Twist and maspin from DCIS to invasive tumor. In distant metastases from bone, brain and lung the frequency of methylation for CCND2, RASSF1A, Twist, RARβ2 and HIN1 was statistically significant different as compared with the primary tumor. The analysis of six cases of paired primary tumors and lymph node metastasis showed same methylation patterns for all but one case. The identification of changes in methylation distribution during breast cancer progression is fundamental not only for a better comprehension of the mechanisms involved in breast carcinogenesis, but because such alterations may represent potential markers for early cancer detection and for a better definition of the prognosis.