Molecular targets for breast cancer therapy and prevention

Bange, Johannes; Zwick, Esther; Ullrich, Axel

doi:10.1038/87872

Cited by 261 publications

(169 citation statements)

References 51 publications

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“…Due to growing disappointment with current therapies for breast cancer, which have not lead to significant alleviation of metastatic disease, more attention has been focused on developing novel targeted therapies (Bange et al, 2001). Major targets are members Values of the relative expression of pERK1/2 expressed as a ratio of total ERK1/2 expression, and corrected for equal loading relative to actin (not shown) indicated below the immunoblots were determined by densitometry, and expressed as proportion of the control values (cells treated with DMSO).…”

Section: Discussionmentioning

confidence: 99%

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

et al. 2004

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One of the major targets for breast cancer therapy is the epidermal growth factor receptor (EGFR) and related receptors, which signal via different signal transduction pathways including the mitogen-activated protein kinase (MAPK) pathway. This study determined whether there is a correlation between EGFR/HER2 status and MAPK (ERK1/2) phosphorylation in breast cancer cells, and how this affects the response to an inhibitor of the receptors. Expression of EGFR, HER2 and phosphorylated ERK1/2 were measured by immunoblotting in a panel of breast cancer cell lines. Several lines expressed high levels of pERK1/2, with no obvious correlation with the level of EGFR/HER2. The EGFR tyrosine kinase inhibitor PKI166 inhibited growth and induced apoptosis in some cells with high levels of growth factor receptors (MDA-MB-468, SUM149, SKBR3), but was less effective in cells that also had high basal ERK1/2 activity (MDA-MB-231). The combination of an inhibitor of MAPK signalling (U0126) and PKI166 produced significantly more inhibition and apoptosis than either agent alone. This suggests that constitutive activation of the MAPK pathway may bypass inhibition of EGFR/HER2 tyrosine kinases, and lead to insensitivity to agents targeting the receptors. However, inhibiting both EGFR/ HER2 and MAPK signalling can result in significant growth inhibition and apoptosis of EGFR-expressing breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

et al. 2004

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“…In the best-characterized example of this approach so far, chronic suppression of inflammation through use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to lower the incidence of colon and breast cancer 125,126 . This antitumour activity seems to occur through inhibition of cyclooxygenase-2 (COX2) [127][128][129] , an enzyme that is involved in the synthesis of pro-inflammatory prostaglandins (see the review by Rajnish Gupta and Raymond DuBois on pp.…”

Section: Targeting the Tumour Organmentioning

confidence: 99%

Putting tumours in context

2001

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The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

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“…Estrogen receptors occur in about two-thirds of breast tumors, and the presence of ER seems to be an important prognostic factor in breast cancer [4]. The more favourable prognosis of ER-positive tumors appears to be due to their better response to anti-hormone therapy as compared with ER-negative tumors [5]. Endocrine therapy for hormone-dependent breast cancers is based on the employment of estrogen antagonists, such as tamoxifen [6], which inhibits the binding of estrogens to their receptors, or aromatase inhibitors, which prevent estrogens synthesis [7].…”

Section: Introductionmentioning

confidence: 99%

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

et al. 2012

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a b s t r a c t SAHA, an inhibitor of histone deacetylase activity, has been shown to sensitize tumor cells to apoptosis induced by TRAIL, a member of TNF-family. In this paper we investigated the effect of SAHA/TRAIL combination in two breast cancer cell lines, the ERaÀpositive MCF-7 and the ERaÀnegative MDA-MB231. Treatment of MDA-MB231 and MCF-7 cells with SAHA in combination with TRAIL caused detachment of cells followed by anoikis, a form of apoptosis which occurs after cell detachment, while treatment with SAHA or TRAIL alone did not produce these effects. The effects were more evident in MDA-MB231 cells, which were chosen for ascertaining the mechanism of SAHA/TRAIL action. Our results show that SAHA decreased the level of c-FLIP, thus favouring the interaction of TRAIL with the specific death receptors DR4 and DR5 and the consequent activation of caspase-8. These effects increased when the cells were treated with SAHA/TRAIL combination. Because z-IEDT-fmk, an inhibitor of caspase-8, prevented both the cleavage of the focal adhesion-kinase FAK and cell detachment, we suggest that activation of caspase-8 can be responsible for both the decrement of FAK and the consequent cell detachment. In addition, treatment with SAHA/TRAIL combination caused dissipation of DJ m , activation of caspase-3 and decrement of both phospho-EGFR and phospho-ERK1/2, a kinase which is involved in the phosphorylation of BimEL. Therefore, co-treatment also induced decrement of phospho-BimEL and a concomitant increase in the dephosphorylated form of BimEL, which plays an important role in the induction of anoikis.Our findings suggest the potential application of SAHA in combination with TRAIL in clinical trials for breast cancer.

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Molecular targets for breast cancer therapy and prevention

Cited by 261 publications

References 51 publications

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

Putting tumours in context

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

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