Estrogen receptor-alpha promoter methylation in sporadic basal-like breast cancer of Chinese women.
ABSTRACT Basal-like breast cancer (BLBC) appears to be characterized by a relatively unfavorable prognosis and lack of a specific therapeutic target. Estrogen receptor-alpha (ERα) has been widely accepted as a prognostic marker and a predictor for endocrine therapy response of breast cancer. This study aimed to clarify the correlation of ERα methylation with the pathogenesis and clinicopathological significance of sporadic BLBC of Chinese women without a family history of the cancer. The methylation of ERα promoter was investigated in genomic DNA of 60 sporadic BLBC with 108 cases of non-BLBC as control by methylation-specific polymerase chain reaction. We also investigated the expression of p53, breast cancer gene (BRCA)-1, and BRCA-2 by immunohistochemistry and analyzed the correlation between ERα methylation and clinicopathological features of BLBC. ERα methylation was observed in 48 of 60 (80.0%) sporadic BLBC, which was significantly higher than in sporadic non-BLBC cancer (47/108, 43.5%; χ2=20.89, p<0.01). No correlation was found between the ERα methylation and age and menopausal status, while it was significantly associated with lymph node metastasis, tumor stage, nuclear p53 accumulation, and BRCA-1 and BRCA-2 expression in sporadic BLBC. The ERα methylation status in basal-like breast cancer was significantly higher than in sporadic non-basal-like breast cancer. It was associated with the lymph node metastasis, tumor stage, p53 nuclear accumulation, and BRCA-1 and BRCA-2 expression in BLBC. It may play an important role in BLBC pathogenesis.
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ABSTRACT: Breast cancer is not a single disease, but rather is composed of distinct subtypes associated with different clinical outcomes. Understanding this heterogeneity is key for the development of targeted cancer-preventative and -therapeutic interventions. Current models explaining inter- and intratumoral diversity are the cancer stem cell and the clonal evolution hypotheses. Although tumor initiation and progression are predominantly driven by acquired genetic alterations, recent data implicate a role for microenvironmental and epigenetic changes as well. Comprehensive unbiased studies of tumors and patient populations have significantly advanced our molecular understanding of breast cancer, but translating these findings into clinical practice remains a challenge.Journal of Clinical Investigation 12/2007; 117(11):3155-63. · 12.81 Impact Factor
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ABSTRACT: Using high-resolution oligonucleotide comparative genomic hybridization arrays, we evaluated chromosomal copy number changes in a series of 16 breast cancers, selected on the basis of highly similar pathologic and molecular features characteristic of the "basal-like" phenotype. Each of these cancers showed numerous gains and losses, reflecting multiple chromosomal rearrangements during the development of these high-grade cancers. Chromosomal losses were particularly prevalent on chromosomal arms 5q, 8p, 9q, 12q, 17p, 19p, and Xq, and gains were commonly seen on chromosomal arms 1q, 8q, and 17q. The regions of high-level amplification (copy number change more than eightfold) on 4q12, 8q23.3, 19p12, and 19q13.2 were particularly remarkable. These regions included candidate oncogenes cKIT, JUND, and AKT2, and immunohistochemistry confirmed that these particular genes were highly expressed in the cancers harboring the specific amplifications. Each of these amplifications was observed only in individual cases, however, and no particular chromosomal alteration appeared to generally characterize this group of cancers. Thus, genomic changes among breast cancers with basal-like features appear to be very heterogeneous. Distinct high-level amplifications may provide new targets for treating some of these cancers, but copy number changes do not reveal a distinctive genomic fingerprint for this proposed class of breast cancers.Cancer genetics and cytogenetics 09/2009; 193(1):29-37. · 1.54 Impact Factor
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ABSTRACT: Although numerous studies have reported that high frequencies of loss of heterozygosity (LOH) at various chromosomal arms have been identified in breast cancer, differential LOH in the neoplastic epithelial and surrounding stromal compartments has not been well examined. Using laser capture microdissection, which enables separation of neoplastic epithelium from surrounding stroma, we microdissected each compartment of 41 sporadic invasive adenocarcinomas of the breast. Frequent LOH was identified in both neoplastic epithelial and/or stromal compartments, ranging from 25 to 69% in the neoplastic epithelial cells, and from 17 to 61% in the surrounding stromal cells, respectively. The great majority of markers showed a higher frequency of LOH in the neoplastic epithelial compartment than in the stroma, suggesting that LOH in neoplastic epithelial cells might precede LOH in surrounding stromal cells. Furthermore, we sought to examine pair-wise associations of particular genetic alterations in either epithelial or stromal compartments. Seventeen pairs of markers showed statistically significant associations. We also propose a genetic model of multi-step carcinogenesis for the breast involving the epithelial and stromal compartments and note that genetic alterations occur in the epithelial compartments as the earlier steps followed by LOH in the stromal compartments. Our study strongly suggests that interactions between breast epithelial and stromal compartments might play a critical role in breast carcinogenesis and several genetic alterations in both epithelial and stromal compartments are required for breast tumour growth and progression.Human Molecular Genetics 10/2001; 10(18):1907-13. · 7.69 Impact Factor