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 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

There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.
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PMID:Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? 1680 39