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

The EphA2 receptor tyrosine kinase is frequently overexpressed in invasive breast cancer cells. Moreover, these malignant cells have unstable cell-cell contacts, which preclude EphA2 from interacting with its ligand, EphrinA1, which is anchored to the membrane of adjacent cells. This defect is important because ligand binding causes EphA2 to transmit signals that negatively regulate tumor cell growth and survival, whereas the absence of ligand binding favors these same behaviors. In our present study, human adenoviral type 5 (HAd) vectors were engineered to express secreted-forms of EphrinA1. These vectors were used to infect MDA-MB-231 human breast cancer cells, or MCF-10A human breast epithelial cells providing matched controls. Infection with HAd-EphrinA1-Fc (HAd vector expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) caused increased EphA2 activation and turnover and consequently decreased tumor cell viability in soft agar assays. Consistent with this observation, infection of MDA-MB-231 cells with HAd-EphrinA1-Fc prevented tumor formation in xenograft models. Furthermore, therapeutic modeling via intratumoral inoculation revealed that HAd-EphrinA1-Fc significantly inhibited subsequent tumor growth as compared to matched controls. These results suggest that targeting of EphA2 with adenoviral vectors may have therapeutic value.
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PMID:Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1. 1535 89

Growth factor receptor bound (Grb)14 is a member of the Grb7 family of src homology (SH)2 domain-containing proteins. These proteins perform both adaptor and modulatory roles in receptor tyrosine kinase (RTK) signaling, although their regulation is poorly understood. In this study, a positive correlation between Grb14 protein expression and ER alpha status in breast cancer cell lines led us to investigate regulation of Grb14 by estradiol and insulin, which synergize in the regulation of breast cancer cell proliferation. In MCF-7 cells maintained in charcoal-stripped serum, Grb14 expression was downregulated by estradiol and increased by the pure anti-estrogen ICI 182780. Under serum-free conditions, insulin enhanced Grb14 expression but this effect was repressed by estradiol when both hormones were used in combination. Using a system in which c-Myc induction drives cell cycle progression independently of estradiol, we demonstrated that Grb14 regulation was specific to estradiol treatment. Finally, we demonstrated a novel functional role for Grb14 whereby its overexpression inhibited not only insulin- but also estrogen-induced cell cycle progression. This was associated with decreased extracellular signal-regulated kinase (Erk)1/2 activation in insulin-stimulated Grb14-overexpressing cells. These data represent the first demonstration of regulation of Grb14 expression levels in response to hormonal stimuli, and are consistent with its role as a repressor of insulin signaling where it is induced as a negative feedback mechanism. A role for Grb14 is also shown in estrogen/insulin crosstalk since estradiol blocks the insulin-induced induction of this protein.
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PMID:Hormonal regulation of the Grb14 signal modulator and its role in cell cycle progression of MCF-7 human breast cancer cells. 1537 66

EphA2, a receptor tyrosine kinase, is elevated in many invasive human breast cancers, and the majority of EphA2 remains unphosphorylated. The successful attachment of ligand EphrinA1 present on the surface of adjacent cells to EphA2 initiates EphA2 phosphorylation leading to its turnover. In vivo efficacy of various approaches targeting EphA2 for breast cancer therapy is usually evaluated in nude mice bearing human breast cancer xenografts. In order to establish an immunocompetent mouse model of breast cancer for EphA2-targeted therapies, we evaluated a mouse breast cancer cell line (MT1A2) for EphA2 expression and phosphorylation. Overexpression of EphA2 was observed in MT1A2 cells and the majority of it remained unphosphorylated signifying that EphA2 in MT1A2 cells behaved similar to that of human breast cancer cells. Human adenovirus subtype 5 (HAd5) vectors expressing secretory forms of EphrinA1 were used for in vitro and in vivo targeting of MT1A2-derived EphA2. MT1A2 cells infected with HAd-EphrinA1-Fc (HAd expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) induced EphA2 activation and its turnover. This led to inhibition in MT1A2 cell colony formation in soft agar and cell viability in monolayer culture. In addition, MT1A2 cells-infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic FVB/n mice at least 32 days postinoculation. Moreover, intratumoral inoculation of FVB/n mice-bearing MT1A2-induced tumors with HAd-EphrinA1-Fc slowed the tumor growth and also resulted in the development of vector-specific immune response. These results indicate that FVB/n mice-bearing MT1A2-induced tumors could serve as an immunocompetent model of breast cancer for EphA2-targeted therapeutic strategies.
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PMID:Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy. 1548 59

The receptor tyrosine kinase HER2 enhances tumor metastasis; however, its role in homing to metastatic organs is poorly understood. The chemokine receptor CXCR4 has recently been shown to mediate the movement of malignant cancer cells to specific organs. Here, we show that HER2 enhances the expression of CXCR4, which is required for HER2-mediated invasion in vitro and lung metastasis in vivo. HER2 also inhibits ligand-induced CXCR4 degradation. Finally, a significant correlation between HER2 and CXCR4 expression was observed in human breast tumor tissues, and CXCR4 expression correlated with a poor overall survival rate in patients with breast cancer. These results provide a plausible mechanism for HER2-mediated breast tumor metastasis and establish a functional link between HER2 and CXCR4 signaling pathways.
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PMID:Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. 1554 24

Molecular target-based drugs have been emerging as a cancer treatment. Clinical trials using the combined approach of radiation therapy and molecular target-based drugs have been performed to evaluate the feasibility of this approach, and improve the response of tumors to radiation. To achieve maximum radiotherapeutic gain, understanding of the interaction of radiation and drugs are indispensable. Preclinical data have already demonstrated synergistic enhancement of radiation-induced cell killing by several molecular target-based drugs. Among these, the effect of drugs that target receptor tyrosine kinase and its signal transduction pathways on radiosensitivity has been intensively investigated. In this review, established and potential molecular targets for potentiation of radiation-induced cell killing are summarized, and preclinical data regarding investigations of new molecular targets for radiosensitization will be introduced. In addition, the results and toxicities of clinical trials using combined radiation therapy and molecular target-based drugs are summarized.
Breast Cancer 2004
PMID:Molecular targets for potentiation of radiation-induced cell killing. 1555 Aug 56

The ERBB2/HER2/NEU receptor tyrosine kinase gene is amplified in up to 30% of human breast cancers. The frequent and specific selection of this receptor kinase gene for amplification in breast cancer implies that it has important normal functions in the mammary gland. To investigate the functions of ErbB2 during normal mouse mammary gland development, we transplanted mammary buds from genetically rescued ErbB2(-/-) embryos that express ErbB2 in the cardiac muscle. ErbB2(-/-) mammary buds transplanted to a wild-type mammary fat pad support outgrowth of an epithelial tree that advances only slowly through the mammary fat pad at puberty. This penetration defect is associated with structural defects in terminal end buds, characterized by a decrease in body cell number, an increased presence of cap-like cells in the prelumenal compartment, and the presence of large luminal spaces. Lobuloalveolar development was not affected in glands that developed from ErbB2(-/-) transplanted tissue. The results may have implications for the aggressive phenotypes associated with ERBB2-overexpressing mammary carcinomas.
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PMID:ErbB2 is required for ductal morphogenesis of the mammary gland. 1556 31

The ErbB2 receptor tyrosine kinase has been implicated as a critical growth factor receptor in both normal development and cancer. Amplification and overexpression of this receptor is observed in 20-30% of all human breast cancers and is inversely correlated with patient survival. Studies with transgenic mice have established that elevated expression of erbB2 in mammary epithelium can directly induce mammary carcinomas. Although these studies confirmed a role for ErbB2 in breast cancer induction, the precise role of ErbB2 in normal mammary gland development remained to be elucidated due to the embryonic lethality associated with the null mutation. Here, we demonstrate that the mammary-specific ablation of erbB2 through Cre-mediated recombination leads to a striking ductal elongation defect. In addition to the observed elongation defect, we noted that branching in the adult mammary gland was also reduced. Despite these perturbations in virgin mammary gland morphogenesis, targeted disruption of erbB2 had little impact on the ability of these animals to lactate. Taken together, these observations indicate that erbB2 plays a critical role in the initial stages of mammary gland morphogenesis.
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PMID:Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth. 1558 Feb 95

Targeting HER2(ErbB-2/neu) overexpressing tumor cells to selectively deliver anticancer agents and thereby reduce host toxicity represents a rational and emerging strategy for the treatment of breast and other epithelial cancers. The extracellular domain of the HER2 receptor tyrosine kinase is readily accessible to systemically administered antibody-based therapeutics, including growth-inhibiting monclonals such as rhuMAbHER2 (trastuzmab/Herceptin) as well as anti-HER2 immunotoxins, antibody-dependent enzyme prodrug therapy (ADEPT), and immune cell recruiting bispecific antibodies. In addition to summarizing recent advances in these antibody-based strategies, this review focuses on preclinical advances in the development of anti-HER2 immunoliposomes (ILs) as a platform technology for targeted drug delivery. Extensive in vitro and in vivo testing including efficacy and tumor uptake studies in multiple human tumor xenograft models now provide conclusive evidence for the superior therapeutic efficacy of anti-HER2 ILs-doxorubicin (dox) over free dox or liposomal (Ls)-dox, and even over combinations of dox and Ls-dox with rhuMAbHER2. As anti-HER2 ILs-dox approaches clinical testing in patients with advanced HER2 overexpressing breast cancer, future applications of this novel targeting strategy will also broaden to include intracellular delivery of other anticancer agents as well as therapeutic nucleic acids (oligonucleotides, genes).
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PMID:Emerging antibody-based HER2 (ErbB-2/neu) therapeutics. 1568 97

Heat shock protein 90 is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins important in breast cancer include the estrogen receptor, the serine-threonine kinases Raf-1 and Akt, the receptor tyrosine kinase ErbB2/Neu, and the hypoxia inducible transcription factor HIF-1alpha. Hsp90 small molecule inhibitors, by interacting specifically with a single molecular target, thus promote the destabilization and eventual degradation of multiple cancer cell survival and growth promoting proteins, and these inhibitors have shown promising anti-tumor activity in preclinical breast cancer model systems. One Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trial. Because of their unique ability to inhibit multiple survival pathways utilized by cancer cells, combination of Hsp90 inhibitors with standard chemotherapeutic agents may dramatically increase in vivo efficacy.
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PMID:Heat shock protein 90 is a rational molecular target in breast cancer. 1568 45

Many studies have suggested an association between overexpression of receptor tyrosine kinases (RTKs) from the EGF receptor (or ErbB) family and breast cancer. The orphan RTK ErbB2/HER2/Neu is highly overexpressed in up to 30% of human breast cancer cases as a consequence of gene amplification. ErbB2/HER2/Neu can be activated by simple overexpression, and its signaling is thought to play an important role in initiation and progression of ErbB2-positive breast cancers. In support of this, ErbB2/HER2/Neu-targeted therapy (the Herceptin antibody) has proven valuable in many of these cases. Other studies also correlate EGF receptor (EGFR) expression with poor prognosis in breast cancer, but follow-up studies suggest that this association is much less robust than with ErbB2, and requires more careful analysis. A particular problem is that EGFR, unlike ErbB2/HER2/Neu, cannot be activated simply by overexpression, its signaling remaining growth factor-dependent under these conditions. It is therefore critical to analyze EGFR signaling activity itself, rather than simply EGFR expression, in order to establish causal links and to identify patients for ErbB-targeted therapies. This distinction between ErbB2/HER2/Neu and EGFR is satisfyingly explained by recent crystallographic studies of ErbB receptor family members that are reviewed here. These structures also provide new insight into how ErbB2/HER2/Neu-targeted and EGFR-targeted therapeutic agents function, and suggest approaches for the development of novel mechanism-based ErbB inhibitors.
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PMID:The EGF receptor family as therapeutic targets in breast cancer. 1568 87


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