Molecular Classification of Breast Carcinomas Using Tissue Microarrays

Callagy, Grace; Cattaneo, Elena; Daigo, Yataro; Happerfield, Lisa; Bobrow, Lynda G.; Pharoah, Paul D.P.; Caldas, Carlos

doi:10.1097/00019606-200303000-00004

Cited by 153 publications

(115 citation statements)

References 24 publications

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“…Together, these results indicate that Sox2 may be expressed in the initial phases of tumourigenesis and then is lost as the tumour develops. Spontaneous human breast tumours are predominantly differentiated luminal subtype (68%) while undifferentiated tumours comprise only 24% of the tumours (Callagy et al, 2003). It is common to assume that the tumour phenotype reflects the cell of origin of that tumour, thus, most natural occurring tumours would be originated in the differentiated cells.…”

Section: Discussionmentioning

confidence: 99%

Sox2 expression in breast tumours and activation in breast cancer stem cells

Leis¹,

Eguiara²,

et al. 2011

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The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires selfrenewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming-like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over-expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation.

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Section: Discussionmentioning

confidence: 99%

Sox2 expression in breast tumours and activation in breast cancer stem cells

Leis¹,

Eguiara²,

et al. 2011

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“…There is now increasing interest in the use of multiple biomarkers, either through immunohistochemical detection of protein, or RNA-based technologies, to refine prognostication in individual patients. [20][21][22] This represents a change from the traditional approach of using single biomarkers and appears to be an inevitable next step in risk assessment and treatment planning for newly diagnosed patients with breast cancer. We currently treat many patients with breast cancer who derive no benefit from their treatment.…”

Section: Discussionmentioning

confidence: 99%

MDM2 protein expression is a negative prognostic marker in breast carcinoma

et al. 2006

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The protein encoded by the MDM2 oncogene inhibits the function of p53, leading to increased cell growth, avoidance of apoptosis, tolerance of genetic instability, and resistance to chemotherapy. The present study was performed to evaluate the relationship between MDM2 protein expression and survival in breast carcinoma. Two series of cases were used in this study: the first to identify the cutoff to be used in the interpretation of MDM2 immunostaining and perform preliminary survival analysis, and a second, independent series, to validate the findings from the first series and to perform multivariate analysis. For both series, archival sections of tissue microarrays were stained with anti-MDM2 antibody (NeoMarkers, Fremont, CA, USA) and MDM2 staining intensity was scored semiquantitatively. In the first series, 49 of 362 (14%) interpretable cases were positive for MDM2 expression, with 35 (10%) showing weak positivity and 14 (4%) strong positivity. Patients with MDM2-positive tumours had a significantly worse disease-specific survival than patients with MDM2-negative tumours (P ¼ 0.0022, 10-year DSS 61% (95% CI: 45-73) vs 73% (95% CI: 67-77)). No significant difference in survival was observed between patients with strongly and weakly MDM2-positive tumours (P ¼ 0.3). Accordingly, in the independent validation series weak and strong MDM2 positivity were combined and considered to be MDM2 positive. MDM2 expression was seen in 230/1747 (13%) interpretable cases in this series, with a significant difference (Po0.0001) in DSS between MDM2-negative and MDM2-positive cases (10 year DSS 58% (95% CI: 51-64) vs 73% (95% CI: 70-75)). MDM2 was an independent prognostic marker (HR ¼ The human MDM2 gene encodes a 491 amino-acid protein that contains a binding domain for the tumour suppressor p53. 1 This 90 kDa nuclear phosphoprotein can form a complex with both mutant and wild-type p53, 2 and takes part in downregulation of p53 functions, promoting the rapid degradation of p53 via a ubiquitin-proteasome pathway. 3-5 MDM2 protein acts as a nuclear-cytoplasmic transporter for the p53 protein. 5 The MDM2 gene is transcriptionally upregulated by p53 5-7 and acts as an oncogene in tissue culture. 5 In human tumours, MDM2 takes part in tumorigenesis through one of the three possible mechanisms: gene amplification, increased transcription or enhanced translation. 5 Overexpression of MDM2 is described in many human cancers, including breast carcinoma. 1,3,8 Overexpression of MDM2 protein correlates with high grade and was found to be an independent negative prognostic marker in human breast cancer in one study. 9 Other investigators observed that MDM2 overexpression correlates with favourable prognostic parameters such as ER overexpression. 10 Studies of MDM2 protein expression in breast carcinoma and its prognostic significance have been based on a limited number of cases, and the results of these studies have been inconsistent, as mentioned above. MDM2 amplification in breast1

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“…Moreover, an alternative approach to gene expression profiling is to use established robust laboratory technology, such as immunocytochemistry on formalin fixed paraffin embedded patient tumour samples. We and others have applied protein biomarker panels, with known relevance to breast cancer, to large numbers of cases using tissue microarrays, exploring the existence and clinical significance of distinct breast cancer classes through clustering approaches [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

A quantifier-based fuzzy classification system for breast cancer patients

Soria

Garibaldi

Green

et al. 2013

Artificial Intelligence in Medicine

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A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. Consensus between unsupervised classification algorithms has been successfully used to categorise patients into these specific groups, but often at the expenses of not classifying the whole set. It is known that fuzzy methodologies can provide linguistic based classification rules. The objective of this study was to investigate the use of fuzzy methodologies to create an easy to interpret set of classification rules, capable of placing the large majority of patients into one of the specified groups. Methods and materials:In this paper, we extend a data-driven fuzzy rule-based system for classification purposes (called 'fuzzy quantification subsethood-based algorithm') and combine it with a novel class assignment procedure. The whole approach is then applied to a well characterised breast cancer dataset consisting of ten protein markers for over 1,000 patients to refine previously identified groups and to present clinicians with a linguistic ruleset. A range of statistical approaches were used to compare the obtained classes to previously obtained groupings and to assess the proportion of unclassified patients.Results: A rule set was obtained from the algorithm which features one classification rule per class, using labels of High, Low or Omit for each biomarker, to determine the most appropriate class for each patient. When applied to the whole set of patients, the distribution of the obtained classes had an agreement of 0.9 when assessed using Kendall's Tau with the original reference class distribution. In doing so, only 38 patients out of 1,073 remain unclassified, representing a more clinically usable class assignment algorithm. Conclusion:The fuzzy algorithm provides a simple to interpret, linguistic rule set which classifies over 95% of breast cancer patients into one of seven clinical groups.

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Molecular Classification of Breast Carcinomas Using Tissue Microarrays

Cited by 153 publications

References 24 publications

Sox2 expression in breast tumours and activation in breast cancer stem cells

Sox2 expression in breast tumours and activation in breast cancer stem cells

MDM2 protein expression is a negative prognostic marker in breast carcinoma

A quantifier-based fuzzy classification system for breast cancer patients

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