Molecular evolution of breast cancer

The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
The Journal of Pathology (Impact Factor: 7.33). 01/2005; 205(2):248-54. DOI: 10.1002/path.1691
Source: PubMed

ABSTRACT Molecular analysis of invasive breast cancer and its precursors has furthered our understanding of breast cancer progression. In the past few years, new multi-step pathways of breast cancer progression have been delineated through genotypic-phenotypic correlations. Nuclear grade, more than any other pathological feature, is strongly associated with the number and pattern of molecular genetic abnormalities in breast cancer cells. Thus, there are two distinct major pathways to the evolution of low- and high-grade invasive carcinomas: whilst the former consistently show oestrogen receptor (ER) and progesterone receptor (PgR) positivity and 16q loss, the latter are usually ER/PgR-negative and show Her-2 overexpression/amplification and complex karyotypes. The boundaries between the evolutionary pathways of well-differentiated/low-grade ductal and lobular carcinomas have been blurred, with changes in E-cadherin expression being one of the few distinguishing features between the two. In addition, lesions long thought to be precursors of breast carcinomas, such as hyperplasia of usual type, are currently considered mere risk indicators, whilst columnar cell lesions are now implicated as non-obligate precursors of atypical ductal hyperplasia (ADH) and well-differentiated ductal carcinoma in situ (DCIS). However, only through the combination of comprehensive morphological analysis and cutting-edge molecular tools can this knowledge be translated into clinical practice and patient management.

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    ABSTRACT: Breast cancer (BC) is a heterogeneous disease that encompasses several distinct entities with remarkably different characteristics. Histological type is one of important BC characteristics. Histological type is associated with differences in epidemiology, diagnostic issues, clinical course, prognosis. When we talk about BC, ductal and lobular carcinoma is usually what we have in mind. However, the other types that comprise less than 10% of BC are also very important. The rarity of many of these neoplasms does not allow large or randomized studies to define the optimal treatment. Many of the descriptions are from case reports and small series. The aim of this retrospective study was to analyze the data on rare breast cancers, to describe their main characteristics, and to calculate survival rates. We believe that the experience of our institution will contribute to the available data about these rare breast cancers and help in better understanding of this subgroup.
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    ABSTRACT: A large number of etiological factors and the complexity of breast cancers present challenges for prevention and treatment. Recently, the emergence of microRNAs (miRNAs) as cancer biomarkers has added an extra dimension to the ‘molecular signatures’ of breast cancer. Bioinformatic analyses indicate that each miRNA can regulate hundreds of target genes and could serve functionally as ‘oncogenes’ or ‘tumour suppressor’ genes, and co-ordinate multiple cellular processes relevant to cancer progression. A number of studies have shown that miRNAs play important roles in breast tumorigenesis, metastasis, proliferation and differentiation of breast cancer cells. This review provides a comprehensive overview of miRNAs with established functional relevance in breast cancer, their established target genes and resulting cellular phenotype. The role and application of circulating miRNAs in breast cancer is also discussed. Furthermore, we summarize the role of miRNAs in the hallmarks of breast cancer, as well as the possibility of using miRNAs as potential biomarkers for detection of breast cancer.
    Biological Reviews 01/2015; DOI:10.1111/brv.12176 · 9.79 Impact Factor
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    ABSTRACT: Gene expression profiling of breast cancer has identified distinct subtypes associated with different clinical outcomes. Metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification. Tissue microarray sections were immunostained for estrogen receptor-alpha (ER-alpha), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-alpha, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected. Immunoreactivity of MMPs and TIMPs in the tumor tissue and in the surrounding stromal tissue was evaluated. Statistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival. We found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.
    BMC Cancer 12/2014; 14(1):959. DOI:10.1186/1471-2407-14-959 · 3.32 Impact Factor