Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Optic nerve formation in mouse involves interactions between netrin-1 at the optic disk and the netrin-1 receptor DCC (deleted in colorectal cancer) expressed on retinal ganglion cell (RGC) axons. Deficiency in either protein causes RGC pathfinding defects at the disk leading to optic nerve hypoplasia (). Here we show that further along the visual pathway, RGC axons in netrin-1- or DCC-deficient mice grow in unusually angular trajectories within the ventral hypothalamus. In heterozygous Sey(neu) mice that also have a small optic nerve, RGC axon trajectories appear normal, indicating that the altered RGC axon trajectories in netrin-1 and DCC mutants are not secondarily caused by optic nerve hypoplasia. Intrinsic hypothalamic patterning is also affected in netrin-1 and DCC mutants, including a severe reduction in the posterior axon projections of gonadotropin-releasing hormone neurons. In addition to axon pathway defects, antidiuretic hormone and oxytocin neurons are found ectopically in the ventromedial hypothalamus, apparently no longer confined to the supraoptic nucleus in mutants. In summary, netrin-1 and DCC, presumably via direct interactions, govern both axon pathway formation and neuronal position during hypothalamic development, and loss of netrin-1 or DCC function affects both visual and neuroendocrine systems. Netrin protein localization also indicates that unlike in more caudal CNS, guidance about the hypothalamic ventral midline does not require midline expression of netrin.
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PMID:Altered midline axon pathways and ectopic neurons in the developing hypothalamus of netrin-1- and DCC-deficient mice. 1055 99

We report the case of an 82-year-old male patient with a > 8-year history of prostate cancer (PrCa), who developed breast adenocarcinoma (BrCa) (Ki-67+ and negative for ER, PR, PSA and HER2/neu) after prolonged (approximately 7-year) anti-androgen (flutamide) monotherapy for locally advanced PrCa. Biochemical and molecular analyses showed hyperestrogenemia (serum estradiol = 266 pg/ml, with normal range < 74 pg/ml), germline BRCA-1 mutation (T to C at nucleotide 3232, in exon 11, causing Glu to Gly change at codon 1038) and chromosome 9 inversion (karyotype of 46,XY with inv(9) (p11q21)). Following bilateral mastectomy without adjuvant systemic therapy, the patient has been disease-free (from both BrCa and PrCa) for > 3 years. In contrast to LHRH-based hormonal therapies for PrCa, anti-androgen monotherapy causes hyper-estrogenemia due to the suppressed negative feedback loop of androgens on LHRH and LH production, stimulation of testicular androgen production and their intracrine transformation to estrogens in peripheral target tissues. In this case report, the hyperestrogenemia may have further increased the BrCa risk in a patient with other risk factors (BRCA-1 mutation and chromosome 9 inversion, which has been previously shown to impinge upon testicular function and intracrine balance of androgens vs. estrogens). This case report illustrates that PrCa patients receiving anti-androgen monotherapy may be at risk of BrCa, in the event of the concomitant presence of other genetically-determined predisposing factors, and indicates the importance of exercising caution against indiscriminate and prolonged use of anti-androgen monotherapy in patients with risk factors for male BrCa.
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PMID:Male breast adenocarcinoma in a prostate cancer patient following prolonged anti-androgen monotherapy. 1515 26

Metastasis to bone is a frequent problem of advanced breast cancer. Particularly breast cancers, which do not express estrogen and progesterone receptors and which have no overexpression/amplification of the HER2-neu gene, so called triple-negative breast cancers, are considered as very aggressive and possess a bad prognosis. About 60% of all human breast cancers and about 74% of triple-negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a therapeutic target. Recently, we could show that bone-directed invasion of human breast cancer cells in vitro is time- and dose-dependently reduced by GnRH analogs. In the present study, we have analyzed whether GnRH analogs are able to reduce metastases of triple-negative breast cancers in vivo. In addition, we have evaluated the effects of GnRH analogs on tumor growth. To quantify formation of metastasis by triple-negative MDA-MB-435 and MDA-MB-231 human breast cancers, we used a real-time PCR method based on detection of human-specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs. To analyze tumor growth, the volumes of breast cancer xenotransplants into nude mice were measured. We could demonstrate that GnRH analogs significantly reduced metastasis formation by triple-negative breast cancer in vivo. In addition, we could show that GnRH analogs significantly inhibited the growth of breast cancer into nude mice. Side effects were not detectable. In conclusion, GnRH analogs seem to be suitable drugs for an efficacious therapy for triple-negative, GnRH receptor-positive human breast cancers to prevent metastasis formation.
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PMID:Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo. 2127 82

Triple-negative breast cancer does not express estrogen and progesterone receptors and there is no overexpression/amplification of the HER2-neu gene. Therefore, this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. About 60% of all human breast cancers express receptors for luteinizing hormone releasing hormone (LHRH, GnRH), which might be used as a target. The LHRH receptor can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone agonists such as AEZS-108 (AN-152), in which doxorubicin is linked to [D-Lys6]LHRH. In the present study we have analyzed by in vitro and in vivo experiments whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in triple-negative human breast cancer cells that express LHRH receptors. LHRH receptor expression in tumor biopsy specimens of triple-negative breast cancers was tested using immunohistochemistry. Cell proliferation was analyzed using alamar blue proliferation assay. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human breast tumors.Thirty-one of 42 triple-negative breast cancers (73.8%) expressed LHRH receptors. We could show that treatment of triple-negative but LHRH-positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro via activation of caspase-3. The antitumor effects were confirmed in nude mice. AEZS-108 (AN-152) inhibited the growth of xenotransplants of triple-negative human breast cancers in nude mice completely, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for an efficacious therapy for triple-negative breast cancers with little toxicity.
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PMID:Targeted chemotherapy for triple-negative breast cancers via LHRH receptor. 2133 48