Triple negative tumours: A critical review

The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Histopathology (Impact Factor: 3.3). 02/2008; 52(1):108-18. DOI: 10.1111/j.1365-2559.2007.02889.x
Source: PubMed

ABSTRACT Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor-positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple-negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re-discovery of basal-like breast cancers, which preferentially show a triple-negative phenotype. Both triple-negative and basal-like cancers preferentially affect young and African-American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple-negative and basal-like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal-like and triple-negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple-negative and basal-like cancers and animal models for these tumour types.

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    • "Adjuvant Trastuzumab therapy, which specifically targets the HER2 receptor, is used to treat ERaÀ/PRÀ/HER2+ tumors and has resulted in positive survival outcomes. In contrast, the ERaÀ/PRÀ/HER2À subtype or triple negative breast cancer, which accounts for 10–17% of all breast cancer cases, and the normal breast-like (basal-like) cancer subtype, which accounts for 15% of the cases, are both without approved targeted therapies [61]. "
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    ABSTRACT: Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and "dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1" (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers.
    Cancer Treatment Reviews 10/2014; 40(10). DOI:10.1016/j.ctrv.2014.10.005 · 6.47 Impact Factor
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    • "Alternatively , FPD-SFN combination therapy could also be employed as antiresistance strategies in cases refractory to trastuzumab or lapatinib. Lastly, TN BC, the most aggressive BC subtype, is characterized by a lack of estrogen, progesterone, and HER-2 receptor expression and with EGFR overexpression [7] [54]. "
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    ABSTRACT: Oncogenic receptor tyrosine kinase (RTK) signaling through the Ras-Raf-Mek-Erk (Ras-MAPK) pathway is implicated in a wide array of carcinomas, including those of the breast. The cyclin-dependent kinases (CDKs) are implicated in regulating proliferative and survival signaling downstream of this pathway. Here, we show that CDK inhibitors exhibit an order of magnitude greater cytotoxic potency than a suite of inhibitors targeting RTK and Ras-MAPK signaling in cell lines representative of clinically recognized breast cancer (BC) subtypes. Drug combination studies show that the pan-CDK inhibitor, flavopiridol (FPD), synergistically potentiated cytotoxicity induced by the Raf inhibitor, sorafenib (SFN). This synergy was most pronounced at sub-EC50 SFN concentrations in MDA-MB-231 (KRAS-G13D and BRAF-G464V mutations), MDA-MB-468 [epidermal growth factor receptor (EGFR) overexpression], and SKBR3 [ErbB2/EGFR2 (HER-2) overexpression] cells but not in hormone-dependent MCF-7 and T47D cells. Potentiation of SFN cytotoxicity by FPD correlated with enhanced apoptosis, suppression of retinoblastoma (Rb) signaling, and reduced Mcl-1 expression. SFN and FPD were also tested in an MDA-MB-231 mammary fat pad engraftment model of tumorigenesis. Mice treated with both drugs exhibited reduced primary tumor growth rates and metastatic tumor load in the lungs compared to treatment with either drug alone, and this correlated with greater reductions in Rb signaling and Mcl-1 expression in resected tumors. These findings support the development of CDK and Raf co-targeting strategies in EGFR/HER-2-overexpressing or RAS/RAF mutant BCs.
    Neoplasia (New York, N.Y.) 08/2013; 15(8):939-51. DOI:10.1593/neo.13804 · 5.40 Impact Factor
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    • "CK5/6, CK14 and EGFR were considered positive if 10% or more tumor cells showed positive membranous expression, and BL immunophenotype was defined by ER/PR/HER2 negativity, and positivity of one or more basal cell markers: CK5/6, CK14 or EGFR [14]. BL morphology was considered positive if all of the characteristic features were present: high histological grade, high mitotic index, syncytial growth pattern, the presence of central areas of tumoral necrosis, pushing borders and dense lymphocytic infiltrate at the periphery of the invasive component [9] [25]. Ki-67 was determined by counting 1000 tumor cells using the Olympus Image Analyser (magnification 400×) at the hot spots or at the periphery of the invasive component, and was expressed as the percentage of positive cells among a total number of 1000 tumor cells [5] (Fig. 1). "
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    ABSTRACT: The aim of this study was to assess Ki-67 in the triple negative breast cancer group (TNBC) in addition to basal like (BL) immunophenotype, BL morphology and conventional clinicopathologic factors, and to demonstrate their prognostic relevance in this group of tumors. Immunohistochemical staining for CK5/6, CK14, EGFR and Ki-67 was performed on 83 formalin-fixed, paraffin-embedded tumor sections. Correlations between categorical variables were studied using the chi-square and the Mann-Whitney U test. For survival analysis, the Kaplan-Meier method, the log-rank test and the Cox proportional hazard regression model were used. The optimal cut-off values for Ki-67 and mitotic count were selected using the ROC (receiver operating characteristic) method. Of the 83 TNBC, 55 (66.3%) had the BL immunophenotype, and 40 (48.2%) had BL morphology. Clinical stage and Ki-67 proliferation index were significantly associated with shorter disease-free survival (DFS) (p=0.002 and p<0.001) and overall survival (OS) (p=0.05 and p=0.025). An independent prognostic relevance regarding DFS and OS was found for clinical stage (p<0.001 and p<0.001), Ki-67 (p=0.008 and p=0.055) and BL morphology concerning DFS (p=0.011). Cellular proliferation measured by Ki-67 has prognostic relevance in TNBC, but further validation of its clinical significance, standardization of assessment and determination of optimal cut-off points is essential for this group of breast tumors.
    Pathology - Research and Practice 03/2013; 209(5):296-301. DOI:10.1016/j.prp.2013.02.012 · 1.56 Impact Factor
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