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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function of the epidermal growth factor receptor (EGFR) family member HER4 remains unclear because its activating ligand, heregulin, results in either proliferation or differentiation. This variable response may stem from the range of signals generated by HER4 homodimers versus heterodimeric complexes with other EGFR family members. The ratio of homo- and heterodimeric complexes may be influenced both by a cell's EGFR family member expression profile and by the ligand or even ligand isoform used. To define the role of HER4 in mediating antiproliferative and differentiation responses, human breast cancer cell lines were screened for responses to heregulin. Only cells that expressed HER4 exhibited heregulin-dependent antiproliferative responses. In-depth studies of one line, SUM44, demonstrated that the antiproliferative and differentiation responses correlated with HER4 activation and were abolished by stable expression of a kinase-inactive HER4. HB-EGF, a HER4-specific ligand in this EGFR-negative cell line, also induced an antiproliferative response. Moreover, introduction and stable expression of HER4 in HER4-negative SUM102 cells resulted in the acquisition of a heregulin-dependent antiproliferative response, associated with increases in markers of differentiation. The role of HER2 in these heregulin-dependent responses was examined through elimination of cell surface HER2 signaling by stable expression of a single-chain anti-HER2 antibody that sequestered HER2 in the endoplasmic reticulum. In the cell lines with either endogenously (SUM44) or exogenously (SUM102) expressed HER4, elimination of HER2 did not alter HER4-dependent decreases in cell growth. These results suggest that HER4 is both necessary and sufficient to trigger an antiproliferative response in human breast cancer cells.
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PMID:Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. 1139 Jun 55

Human epidermal growth factor receptors (HER/erbB) constitute a family of four cell surface receptors involved in transmission of signals controlling normal cell growth and differentiation. A range of growth factors serve as ligands, but none is specific for the HER2 receptor. HER receptors exist as both monomers and dimers, either homo- or heterodimers. Ligand binding to HERI, HER3 or HER4 induces rapid receptor dimerization, with a marked preference for HER2 as a dimer partner. Moreover, HER2-containing heterodimers generate intracellular signals that are significantly stronger than signals emanating from other HER combinations. In normal cells, few HER2 molecules exist at the cell surface, so few heterodimers are formed and growth signals are relatively weak and controllable. When HER2 is overexpressed multiple HER2 heterodimers are formed and cell signaling is stronger, resulting in enhanced responsiveness to growth factors and malignant growth. This explains why HER2 overexpression is an indicator of poor prognosis in breast tumors and may be predictive of response to treatment. HER2 is a highly specific and promising target for new breast cancer treatments. The recombinant human anti-HER2 monoclonal antibody (rhuMAb-HER2, trastuzumab, Herceptin) induces rapid removal of HER2 from the cell surface, thereby reducing its availability to heterodimers and reducing oncogenicity.
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PMID:The basic biology of HER2. 1152 19

Recent studies have established that growth factors and their receptors play an essential role in regulating the proliferation of epithelial cells. Abnormalities in the expression, structure, or activity of their proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, c-erbB2 encodes the human epidermal growth factor receptor 2 (HER2), which is overexpressed or amplified or both in several human malignancies including breast, ovarian, and colon cancers. Tumor cells must use the process of vascularization (angiogenesis) for productive growth and metastasis. Overexpression of HER2 in human tumor cells is closely associated with increased angiogenesis and expression of vascular endothelial growth factor (VEGF). Indeed, when the VEGF pathway is inhibited, tumor growth is suppressed. The anti-HER2 blocking antibody trastuzumab has been shown to inhibit tumor cell growth and VEGF expression. Cancer cell invasiveness can be promoted, even in the absence of HER2 overexpression, by transregulation of HER2 by heregulins that bind to HER3 and HER4. Accordingly, heregulin beta1 regulates the expression and secretion of VEGF in breast cancer cells, and trastuzumab inhibits heregulin-mediated angiogenesis both in vitro and in vivo. Thus, potential upregulation of VEGF in cancer epithelial cells likely supports angiogenesis, sustaining and promoting survival and metastasis of tumor cells.
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PMID:The role of HER2 in angiogenesis. 1170 93

The mechanism underlying the diverse functions of Heregulin-beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptors 3 (HER3) and 4 (HER4), is not well understood but it is believed to involve induced changes in the expression of specific cellular gene products, their modification, or both. We performed differential display screening in cells grown in the presence or absence of HRG to identify genes whose expression may be modulated by HRG. Isolates from one cDNA clone were 100% identical to human heat shock protein-70 (Hsp70), a protein that functions as a molecular chaperone. We identified Hsp70 as one of the HRG-inducible gene products in human breast cancer cells. In addition, human breast tumor samples contained more Hsp70 protein than did samples from adjacent normal tissue. Because Hsp70 acts as a molecular chaperone with cell survival function, our findings suggest that stimulation of Hsp70 expression is a potential mechanism of protein redistribution in growth-factor-activated cells.
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PMID:Heregulin up-regulates heat shock protein-70 expression in breast cancer cells. 1217 71

HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.
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PMID:Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. 1261 Jun 29

The EGF Receptor (EGFR), the first transmembrane receptor tyrosine kinase cloned and sequenced, and its closely related family members HER2, HER3, and HER4, play myriad roles in mammalian growth and development. Receptor activation involves ligand binding to separate receptors followed by formation of active dimers. These receptors can signal as homodimers or they can subtly alter signaling output by heterodimerizing with other family members. Adding complexity, these receptors with varying specificity bind at least 10 ligands from two ligand families, the EGF and neuregulin/heregulin families. This signaling system's impact on human neoplasia is underscored by the following: i.) EGFR is overexpressed or activated by autocrine or paracrine growth factor loops in at least 50% of epithelial malignancies; ii.) HER2 is amplified and dramatically overexpressed in approximately 20%-25% or breast cancers; iii) HER3 and HER4 are variably expressed in breast and other cancers. Overexpression and/or activation of EGFR, HER2 and HER3 has been correlated with poor tumor prognosis; antibody and small molecule inhibitors of their activity are being tested as therapy in cancer patients. However, the signaling complexity engendered by four interacting receptors and ten ligands makes it difficult to definitively measure receptor signaling output in human tumors and even makes mechanistic studies of the family's role in normal physiology and neoplastic transformation a challenge. In spite of the literature's emphasis on growth control, activation by some EGF receptor family member ligands can produce tumor cell differentiation, characterized by growth cessation and differentiation gene product synthesis. The present work delineates a role for HER4 in breast cancer cell differentiation and demonstrates that HER4 is both necessary and sufficient to produce an anti-proliferative signal. These
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PMID:The EGF receptor family--multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4. 1281 28

EGFr/HER1 and c-erbB-2/HER2 expression are associated with poor prognosis in breast cancer. The type I receptor tyrosine kinase (RTK) family to which they belong has four members (HER1-4). In this study, expression of HER1-4 and oestrogen receptor (ER) expression were determined by immunohistochemistry in 220 breast carcinomas. Elevated expression of HER1 was observed in 16.4%, HER2 in 22.8%, HER3 in 17.5%, and HER4 in 11.9% of these tumours. Patients whose tumours overexpressed HER1, 2 or 3 had reduced survival (p= <0.001), whereas those whose tumours overexpressed HER4 had increased survival (p=0.013); 38.6% of cases overexpressed one or more of HER1, 2 or 3. HER4 was rarely overexpressed with other HERs (1.4% of cases). Cox's multiple regression analysis demonstrated that overexpression of HER1/2/3, HER4, and standard prognostic indicators independently affected survival. HER1-3 expression was related to ER negativity (p<0.0001, chi2). Patients with ER-positive, HER1-3-positive tumours had a significantly poorer survival (p<0.001) than those with ER-positive/HER-negative or HER4-positive tumours. Expression of HER RTKs displays complex interactions between different family members. There is a strong interaction, in terms of survival, between HER expression and ER expression. The development of HER-targeted agents (eg Herceptin, Iressa), and agents targeted at the downstream signalling pathways, therefore provides new possibilities in the treatment of breast cancer.
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PMID:Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. 1284 22

We have recently studied expression of estrogen receptors and the growth inhibitory effects of antiestrogens on human myeloma cells. In myeloma chemotherapy, Antiestrogens in combination with other chemotherapeutic agents, may have applications in which melphalan/predonisolone still remains the standard treatment. In this study, we examined expression of HER family molecules in myeloma cells to clarify the possible usage of anti-HER2-monoclonal antibody in the treatment of myeloma. Although the mRNA levels of HER family genes analyzed by RT-PCR were significantly lower in myeloma cells than breast cancer cells, some cell lines expressed a certain amount of HER2 and HER4 proteins. In addition, an anti-HER2 monoclonal antibody, rhumAbHER2, caused significant growth inhibition in six out of eight myeloma cell lines studied and these inhibitory effects were similar to those in the breast cancer cells studied previously. The rhumAbHER2 induced up-regulation of p21 family CDK-Is (cyclin dependent kinase inhibitors) and down-regulation of VEGF genes. Moreover, combination treatment with antiestrogen had an additive growth inhibitory effect. Such analyses may provide for use of rhumAbHER2 in myeloma treatment for the future.
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PMID:Expression of HER family receptors and effects of anti-HER2-antibody on human myeloma cell lines. 1296 96

HER gene family (HER1-HER4) encodes structurally similar transmembrane proteins (EGFR, HER2, ErB-3, and ErB-4) with tyrosine kinase activity. Dimerised on binding with a number of ligands, including epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha), these proteins stimulate epithelial cell proliferation. HER2 and EGFR overexpression is detected in the cells of many tumours, mainly in breast, lung and oral cancer and may be connected with HER2 gene amplification or point mutations as well as with the presence of overactive polymorphic forms of HER1 gene. The first medication of a proved efficacy in breast cancer treatment was trastuzumab (Herceptin)--monoclonal antibody against HER2 protein. Trastuzumab was effective only in the case of patients with high HER2 expression evaluated by immunohistochemical methods and with gene amplification ascertained by fluorescence in situ hybridisation assays. In non-small-cell lung cancer (NSCLC), HER2 overexpression was detected only in a few cases. Therefore, trastuzumab treatment seems to be problematic in NSCLC patients. A small molecule quinazoline (erlotinib, Tarceva) is a promising therapeutic agent selectively blocking EGFR. Phase III Tarceva clinical trail in NSCLC patients showed that their survival is prolonged and that the medication acts together with other chemotherapeutic agents like cisplatin and gemcitabine.
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PMID:Anti-HER therapeutic agents in the treatment of non-small-cell lung cancer. 1531 69

We measured the expression of ERM gene, a nuclear transcription factor belonging to the ets family, in a series of 364 unselected primary breast cancers from patients who underwent locoregional surgery in the Centre Oscar Lambret between May 1989 and December 1991. The expression of ERM was quantified with a real-time one-step reverse transcription-PCR assay based on the 5'-nuclease activity of the TaqDNA polymerase and with an Abi Prism 7700 Sequence Detector System (Applied Biosystems, Courtaboeuf, France). ERM was positively correlated (Spearman test) to epidermal growth factor receptor (EGFR; P < 0.001, r = 0.296) and to histoprognostic grading (P = 0.044, r = 0.112), whereas it was negatively correlated to estradiol receptors (P = 0.019, r = -0.124), HER3 (c-erbB-3; P = 0.01, r = -0.135), and HER4 (c-erbB-4; P = 0.003, r = -0.154). Using the chi2 test, a positive relationship was found between the expression of ERM and EGFR (chi2 = 7.795, P = 0.007). In overall survival studies, Cox univariate analyses demonstrated a prognostic value of ERM (P = 0.006; risk ratio, 2.95) besides the classical prognostic factors histoprognostic grading, node involvement, tumor size, estradiol receptors, progesterone receptors, EGFR, HER3, and HER4. In multivariate analyses, ERM preserved its prognostic value (P = 0.004; risk ratio, 3.779) together with histoprognostic grading, tumor size, estradiol receptors, and progesterone receptors. In relapse-free survival studies, univariate analyses demonstrated that histoprognostic grading, node involvement, tumor size, and HER4 were prognostic factors. These parameters, except histoprognostic grading, retained their prognostic value in multivariate analyses. This study demonstrates for the first time that ERM gene expression is an independent adverse prognostic factor for overall survival in breast cancer patients.
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PMID:Prognostic value of ERM gene expression in human primary breast cancers. 1553 5


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