Targeting the oestrogen receptor, HER2 (human epidermal growth factor receptor 2) and vascular endothelial growth factor has markedly improved breast cancer therapy. New targeted therapeutic approaches to induction of apoptosis or inhibition of antiapoptosis, cell cycle progression, signal transduction and angiogenesis are described. The molecular pathways and their inhibitory or repair mechanisms are discussed in the preclinical and clinical settings. IntroductionTreatment of early-stage breast cancer requires a multimodality approach to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain growth and invasion of carcinoma cells is critical to effective treatment of breast cancer [1,2].Targeting the oestrogen receptor (ER) is the oldest molecular targeted therapy approach, and widespread use of the selective ER modulator tamoxifen in breast cancer is responsible for major improvements in cure rates, quality of life and disease prevention during the past 25 years. Targeting both HER2 (human epidermal growth factor receptor 2) with trastuzumab and the vascular endothelial growth factor (VEGF) with bevacizumab in combination with chemotherapy has become a further milestone of molecular targeted therapy [3][4][5]. However, intrinsic and acquired resistance to endocrine and/or cytostatic treatments is still a common feature that limits the benefits of these novel therapeutic strategies. Therefore, clinical trials of endocrine or cytotoxic therapies combined with growth factor pathway inhibitors or their downstream signalling elements are warranted; such approaches may allow us to improve upon the current standard of care for breast cancer patients [6]. Unfortunately, despite encouraging preclinical data, some of these combinations have yielded disappointing results in the clinical setting [7].This review describes and critically discusses targeted therapies for induction of apoptosis or inhibition of antiapoptosis, cell cycle progression, signal transduction and angiogenesis (Fig. 1). Table 1 summarizes both finished and ongoing studies in this area. Induction of apoptosis and inhibition of antiapoptosisApoptosis is a precisely regulated and evolutionarily conserved programme of cell suicide, which plays important roles during embryogenesis and immunology. Disturbances in the physiological programme of apoptosis prolong the life of cells and thereby promote carcinogenesis. Consequently, apoptosis is frequently diminished in cancer cells, supposedly caused by a dominance of anti-apoptotic proteins in malignant tumours. Regulation of apoptosis is complex, but two distinct pathways can be identified: the intrinsic apoptotic pathway, also referred to as p53-mitochondrial pathway; and the extrinsic pathway, which is activated through 'death receptors' and their corresponding ligands (for example, the death-inducing cytokine TRAIL [tumour necrosis factorrelated apoptosis inducing ligand]). TRAIL is a transmembrane protein that is cleaved by proteases to release a s...

Gains of chromosomes 7p and 8q are associated with poor prognosis among oestrogen receptor-positive (ER þ ) stage I/II breast cancer. To identify transcriptional changes associated with this breast cancer subtype, we applied suppression subtractive hybridisation method to analyse differentially expressed genes among six breast tumours with and without chromosomal 7p and 8q gains. Identified mRNAs were validated by real-time RT -PCR in tissue samples obtained from 186 patients with stage I/II breast cancer. Advanced statistical methods were applied to identify associations of mRNA expression with distant metastasis-free survival (DMFS). mRNA expression of the key enzyme of cholesterol biosynthesis, squalene epoxidase (SQLE, chromosomal location 8q24.1), was associated with ER þ 7p þ /8q þ breast cancer. Distant metastasis-free survival in stage I/II breast cancer cases was significantly inversely related to SQLE mRNA in multivariate Cox analysis (Po0.001) in two independent patient cohorts of 160 patients each. The clinically favourable group associated with a low SQLE mRNA expression could be further divided by mRNA expression levels of the oestrogen-regulated zinc transporter LIV-1. The data strongly support that SQLE mRNA expression might indicate high-risk ER þ stage I/II breast cancers. Further studies on tumour tissue from standardised treated patients, for example with tamoxifen, may validate the role of SQLE as a novel diagnostic parameter for ER þ early stage breast cancers.

IntroductionBreast cancer is the most common form of cancer in women from developed countries. Axillary lymph node status is widely accepted as an important parameter for assessing prognosis in breast cancer patients. However, recurrence and death also occur in patients with nodenegative breast cancer (NNBC). A recurrence rate of 30% may be expected during the first 5 years after diagnosis. Prognostic factors such as tumour size, tumour grading, hormone receptor status, age, histology, ploidy and proliferation index are used to define subgroups of high-risk NNBC patients [1][2][3][4][5][6][7][8]. Despite the availability of these prognostic markers, high-risk NNBC patients cannot be identified with sufficient accuracy. This has led to a search for new and possibly stronger prognostic markers in order to define new subgroups and to facilitate decision-making with respect to appropriate therapy [2,3,9]. AGCN = average gene copy number; CART = Classification and Regression Trees; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; DFS = disease-free survival; NNBC = node-negative breast cancer; FEC = fluorouracil, epirubicin, cyclophosphamide; OS = overall survival; PCR = polymerase chain reaction. Breast Cancer ResearchVol 5 No 2 Schlotter et al. AbstractBackground: At present, node-negative, high-risk breast cancer patients cannot be identified with sufficient accuracy. Consequently, further strong prognostic factors are needed.

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