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

The breast cancer gene BRCA1 has previously been cloned from both human and mouse. We cloned a fragment of the rat Brca1 homologue in order to map it and explore its biological function. Partial cDNA fragments of the rat Brca1 homologue were isolated by RT-PCR. Sequence analysis revealed that the RING-finger domain is well conserved among rat, mouse and human. Rat Brca1 mRNA was expressed in most tissues studied with the highest level in testis, consistent with studies in human and mouse. Next, intron 6-containing DNA fragments were amplified by PCR from WKY and WF rat strains. The splicing sites between exon 6 and exon 7 are conserved between rat and human. Partial sequencing of the rat Brca1 intron 6 revealed a polymorphism of a pentanucleotide TTTTG repeat between the WKY and WF strains. With this intragenic microsatellite marker, we were able to map precisely the rat Brca1 gene to chromosome 10 using a genetic linkage study of (WKY x WF)F1 x WF backcross rats. Brca1 cosegregates with marker BAND3A, and is flanked by R5123 and R5842. Using this polymorphic marker, we also investigated the loss of heterozygosity (LOH) of the Brca1 microsatellite marker in carcinogen- or radiation-induced mammary carcinomas in (WF x F344)F1 female rats. No LOH or somatic microsatellite instability was detected in 18 DMBA-induced tumors studied. Only one LOH of the F344 allele was observed in 26 radiation-induced tumors tested. Ribonuclease protection assays demonstrated that Brca1 mRNA levels are similar in normal rat mammary glands and mammary carcinomas of various etiologies, including those induced by DMBA, NMU, activated-neu and activated-ras oncogenes.
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PMID:Cloning, genetic mapping and expression studies of the rat Brca1 gene. 876 10

The progression of human breast cancer is often associated with a loss of estrogen dependence for growth, a resistance to estrogen antagonists such as tamoxifen, and the metastatic spread of the disease to secondary sites. Cell lines developed from such advanced breast tumors are often metastatic in athymic mice, show a loss of estrogen receptor mRNA and protein (ER-), and do not respond to 17beta-estradiol. However many advanced human breast tumors do express significant amounts of ER transcript, especially when analyzed by more sensitive methods of detection including RT-PCR and Ribonuclease Protection Assay (RPA). No metastatic, ER+breast tumor cell line has previously existed to examine the role of ER in metastatic progression and acquired drug (tamoxifen) resistance. The GI-101A cell line was recently developed from a metastatic breast tumor xenograft and is both tumorogenic and metastatic to the lungs and lymph node when injected into athymic mice, a pattern similar to that seen in patients. While Western blot analysis initially indicated that GI-101A was ER-, analysis of ER mRNA by RT-PCR and RPA have demonstrated the expression of ER (as well as EGF receptor and neu oncogene) transcripts. Functional ER in GI-101A was confirmed by a clear growth response to 17beta-estradiol in culture. Optimal 17beta-estradiol concentrations were significantly lower for GI101A than for MCF-7 (1 n m as opposed to >/=10 n m), and GI-101A growth was inhibited at 17beta-estradiol concentrations above 10 n m. Unlike MCF-7 cells, GI-101A shows constitutive expression of pS2 protein in hormone depleted media with no apparent induction by 17beta-estradiol supplimentation, as well as a resistance to the anti-estrogen tamoxifen at concentrations up to 10 n m. Finally, ER transcripts which likely represent an alternately spliced ER variant which has previously been shown to encode a constitutively active ER protein have been detected in GI-101A at levels similar to the wild type transcript, and offer a possible mechanism for estrogen independence, tamoxifen resistance, and constitutive pS2 expression.
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PMID:A metastatic breast tumor cell line, GI-101A, is estrogen receptor positive and responsive to estrogen but resistant to tamoxifen. 1032 49