Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice
ABSTRACT Triple negative breast carcinomas (TNBCs) are a group of primary breast tumors with aggressive clinical behavior. Most TNBCs possess a basal phenotype (BP) and show varying degrees of basal cytokeratin and myoepithelial marker expression. The importance of recognizing these tumors came to light largely as the result of gene expression profiling studies that categorized breast cancer into 3 major groups. Two of these groups are defined by their respective expression of estrogen receptor and HER2. TNBCs represent a third group and are defined by negativity for hormone receptors and HER2. TNBCs currently lack effective targeted therapies and are frequently resistant to standard chemotherapeutic regimens. These tumors tend to occur in premenopausal women and members of specific ethnic groups and a subset are associated with heritable BRCA1 mutations. For patients with sporadic TNBCs and BP tumors, BRCA1 dysfunction seems to play a major role in the development and progression of disease. The pathologist's role in the diagnosis and characterization of TNBCs and BP tumors is currently being defined as we are acquiring knowledge of the biologic and genetic underpinnings that drive this heterogeneous group of diseases. This review will provide a historical prospective on TNBCs and tumors that express basal cytokeratins and myoepithelial makers. Additionally, we will discuss the molecular biologic, genetic and pathologic aspects of these tumors. Guidelines will be provided on how to best approach the diagnosis of these cases and on what input pathologists should provide clinicians to help develop optimal therapeutic and preventative strategies against this aggressive group of breast cancers.
- SourceAvailable from: Julian Philip Whitelegge
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- "In this study, we have identified a rich source of hydrophobic proteins from selected human tumors and cell lines. Many of these proteins have known important cellular functions, including heat shock proteins (Soo et al., 2008), translation elongation factors (White- Gilbertson et al., 2008), EGFR (Charpidou et al., 2008), cytokeratin (Diaz et al., 2007), CD44 (Ginestier et al., 2007), cadherin (Wang et al., 2008), mitochondrial aldehyde dehydrogenase (Croker et al., 2008), endothelial cell growth factors (Mohammed et al., 2007; Relf et al., 1997), mucin (Rubinstein et al., 2009), and annexin (Imai et al., 2008). "
ABSTRACT: It is widely believed that discovery of specific, sensitive and reliable tumor biomarkers can improve the treatment of cancer. The goal of this study was to develop a novel fractionation protocol targeting hydrophobic proteins as possible cancer cell membrane biomarkers. Hydrophobic proteins of breast cancer tissues and cell lines were enriched by polymeric reverse phase columns. The retained proteins were eluted and digested for peptide identification by nano-liquid chromatography with tandem mass spectrometry using a hybrid linear ion-trap Orbitrap.Hundreds of proteins were identified from each of these three specimens: tumors, normal breast tissue, and breast cancer cell lines. Many of the identified proteins defined key cellular functions. Protein profiles of cancer and normal tissues from the same patient were systematically examined and compared. Stem cell markers were overexpressed in triple negative breast cancer (TNBC) compared with non-TNBC samples. Because breast cancer stem cells are known to be resistant to radiation and chemotherapy, and can be the source of metastasis frequently seen in patients with TNBC, our study may provide evidence of molecules promoting the aggressiveness of TNBC.The initial results obtained using a combination of hydrophobic fractionation and nano-LC mass spectrometry analysis of these proteins appear promising in the discovery of potential cancer biomarkers. When sufficiently refined, this approach may prove useful for early detection and better treatment of breast cancer.Journal of Proteomics & Bioinformatics 01/2010; 3(2):1-10. DOI:10.4172/jpb.1000118
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- "In a subsequent study, Hedenfalk et al (2003) proposed novel classes for the familial non-BRCA1/BRCA2 breast tumours and a different expression profile to those of the BRCA1-and BRCA2-associated tumours reported earlier (Hedenfalk et al, 2003). More recently, it has been suggested that most tumours arising in BRCA1 mutation carriers display a basal-like phenotype, with the percentages reported ranging from 44 to almost 100% (Diaz et al, 2007; Melchor and Benitez, 2008). It is not yet known whether there are differences in the molecular or clinical characteristics within BRCA1 or between BRCA1 and sporadic basal-like tumours. "
ABSTRACT: Gene expression profiling has distinguished sporadic breast tumour classes with genetic and clinical differences. Less is known about the molecular classification of familial breast tumours, which are generally considered to be less heterogeneous. Here, we describe molecular signatures that define BRCA1 subclasses depending on the expression of the gene encoding for oestrogen receptor, ESR1. For this purpose, we have used the Oncochip v2, a cancer-related cDNA microarray to analyze 14 BRCA1-associated breast tumours. Signatures were found to be molecularly associated with different biological processes and transcriptional regulatory programs. The signature of ESR1-positive tumours was mainly linked to cell proliferation and regulated by ER, whereas the signature of ESR1-negative tumours was mainly linked to the immune response and possibly regulated by transcription factors of the REL/NFkappaB family. These signatures were then verified in an independent series of familial and sporadic breast tumours, which revealed a possible prognostic value for each subclass. Over-expression of immune response genes seems to be a common feature of ER-negative sporadic and familial breast cancer and may be associated with good prognosis. Interestingly, the ESR1-negative tumours were substratified into two groups presenting slight differences in the magnitude of the expression of immune response transcripts and REL/NFkappaB transcription factors, which could be dependent on the type of BRCA1 germline mutation. This study reveals the molecular complexity of BRCA1 breast tumours, which are found to display similarities to sporadic tumours, and suggests possible prognostic implications.British Journal of Cancer 10/2009; 101(8):1469-80. DOI:10.1038/sj.bjc.6605275 · 4.82 Impact Factor
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ABSTRACT: Advances in the field of Molecular Biology have led to regroup the breast carcinomas several types according to different gene expression profiles. This molecular classification seems to show much greater clinical significance that the morphological classification, more prognostic and predictive of response to the different treatments. It also enables discover cases of hereditary carcinoma without other criteria for suspicion and facilitates research on new therapeutic targets.