Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A biologically aggressive subset of human breast cancers has been demonstrated to overexpress fatty acid synthase (FAS), the key enzyme of endogenous FA biosynthesis. This breast cancer-specific activation of FAS-dependent lipogenesis, an anabolic-energy-storage pathway of minor importance in normal cells, would render breast cancer cells more vulnerable to anti-metabolite interventions with FAS as therapeutic target. Not surprisingly, pharmacological inhibitors of FAS have been reported to produce both cytostatic and cytotoxic effects in human breast cancer cells, as well as to suppress DNA replication. However, the signal transduction pathway(s) that link FAS hyperactivity and breast cancer cell growth has been unresolved. Here, we have attempted to provide a systematic approach to assess the role of FAS signaling on the survival and proliferation of human breast cancer cells. First, we assessed the level of FAS protein in a panel of human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-435, ZR-75B, T47-D, BT-474, and SK-Br3). FAS expression was graded from ++++ (overexpression) in SK-Br3 cells to + (very low expression) in MDA-MB-231 cells. No correlation was noted between FAS overexpression and estrogen receptor (ER) or progesterone receptor (PR) status, whereas a positive correlation was found between high levels of FAS expression and the amplification and/or overexpression of HER-2/neu oncogene. Because metabolic adaptation of breast cancer cells to the ambient fatty acid concentration may be relevant to the goal of utilizing FAS inhibition as a chemotherapeutic target, we evaluated the effect of exogenous dietary fatty acids on the cytotoxicity resulting from the inhibition of FAS activity. Pharmacological inhibition of FAS activity by the natural antibiotic cerulenin [(2S,3R)-2,3-epoxy-4-oxo-7E,10E-dodecadienamide] resulted in a dose-dependent cytotoxicity which positively paralleled the endogenous level of FAS. Supraphysiological levels of exogenous oleic acid (OA), a omega-9 monounsaturated fatty acid synthesized from a primary-end product of FAS palmitate, significantly diminished cell toxicity caused by cerulenin. Indeed, OA exposure significantly reduced FAS activity and expression by 55% in FAS-overexpressing SK-Br3 cells. omega-3 (alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid) and omega-6 (linoleic acid and arachidonic acid) polyunsaturated fatty acids (PUFAs), however, were unable to rescue breast cancer cells from cerulenin-induced cytotoxicity. Pharmacological blockade of FAS activity in FAS-overexpressing SK-Br3 cells resulted in apoptosis as determined by an enzyme-linked immunosorbent assay for histone-associated DNA fragments, and confirmed by TUNEL DNA-end labeling experiments. We further characterized signaling molecules that participate in the cellular events that follow inhibition of FAS activity and precede apoptosis in breast cancer cells. In SK-Br3 cells, cerulenin-induced inhibition of FAS activity resulted in down-regulation of p53, and up-regulation of cyclin-dependent kinase inhibitor (CDKi) p21WAF1/CIP1. Treatment with cerulenin or a novel small-molecule inhibitor of FAS C75 resulted in a dramatic accumulation of CDKi p27KIP1, which was accompanied by a noteworthy translocation of p27KIP1 from cytosol to cell nuclei. Strikingly, FAS inhibition also caused a significant activation of the Raf-mitogen-activated protein kinase (MEK) extracellular signal-regulated kinase (ERK1/2) cell survival pathway. Interestingly, we demonstrated that inhibition of FAS activity increased the nuclear-to-cytoplasmic ratio of BRCA1, a breast cancer tumor suppressor protein, as well as it induced a nuclear translocalization of the anti-apoptotic nuclear transcription factor-kappaB (NF-kappaB). In conclusion, here we demonstrate that: a) breast cancer cells retain dependence on endogenous fatty acid synthesis and sensitivity to FAS inhibition in the presence of supraphysiological levels of dietary fatty acids, supporting the notion that FAS inhibition may be useful in treFAS inhibition may be useful in treating breast cancer in vivo; b) endogenous fatty acid synthesis is functional in breast cancer cells and is vital since its pharmacological inhibition is cytotoxic by promoting apoptosis, and c) specific blockade of FAS activity induces the accumulation, activation, and/or cellular relocalization of multiple and diverse pro- and anti-apoptotic signaling pathways, suggesting that p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB play a novel role in the breast cancer cell response to a metabolic stress after perturbation of FAS-dependent de novo fatty acid biosynthesis.
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PMID:Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB. 1476 44

Overexpression of the lipogenic enzyme fatty acid synthase (FAS) is a common molecular feature in subsets of sex-steroid-related tumors including endometrium and breast carcinomas that are associated with poor prognosis. Pharmacological inhibition of tumor-associated FAS hyperactivity is under investigation as a chemotherapeutic target. We examined the effects of the mycotoxin cerulenin (a covalent FAS inactivator), and the novel small compound C75 (a slow-binding FAS inhibitor) on estradiol (E2)- and tamoxifen (TAM)-stimulated ER-driven molecular responses in Ishikawa cells, an in vitro model of well-differentiated human endometrial carcinoma. We evaluated the effects of FAS inhibition on E2- and TAM-induced estrogen receptor (ER) transcriptional activity by using transient cotransfection assays with an estrogen-response element reporter construct (ERE-Luciferase). Antiestrogenic effects of cerulenin and C75 were observed by dose-dependent inhibition of E2-stimulated ERE-dependent transcription, whereas FAS inhibitors did not significantly increase the levels of ERE transcriptional activity in the absence of E2. Moreover, pharmacological blockade of FAS activity completely abolished TAM-stimulated ERE activity. To address the reliability of transient transfection assays, the effects of FAS inhibitors on E2-inducible gene products were evaluated. FAS blockade induced a dose-dependent decrease in E2-inducible alkaline phosphatase activity. E2-stimulated accumulation of progesterone receptor (PR) and HER-2/neu oncogene was abolished in the presence of FAS blockers. FAS inhibition also resulted in a marked downregulation of E2-stimulated ERalpha expression, and noticeably impaired E2-induced ERalpha nuclear accumulation. A dose-dependent decrease in cell proliferation and cell viability was observed after FAS blockade. A Cell Death ELISA, detecting DNA fragmentation, demonstrated that FAS inhibitors stimulated apoptosis of Ishikawa cells. The analysis of critical E2- and TAM-related cell cycle proteins revealed an increase of both the expression and the nuclear accumulation of cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1 following FAS inhibition. To rule out non-FAS cerulenin- and C75-related effects, we finally monitored ER signaling after silencing of FAS gene expression using the highly sequence-specific mechanism of RNA interference (RNAi). The concentrations of E2 and TAM inducing half-maximal ERE activity (EC50) dramatically increased (>100 times) in FAS RNAi-transfected Ishikawa cells. Moreover, depletion of FAS by RNAi also caused loss of ERalpha expression, downregulation of PR, and accumulation of p21WAF1/CIP1 and p27Kip1 in E2-stimulated Ishikawa cells. If chemically stable FAS inhibitors or cell-selective vector systems able to deliver RNAi targeting FAS gene demonstrate systemic anticancer effects in vivo, our results render FAS as a novel target for the prevention and treatment of endometrial carcinoma.
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PMID:Inhibition of tumor-associated fatty acid synthase activity antagonizes estradiol- and tamoxifen-induced agonist transactivation of estrogen receptor (ER) in human endometrial adenocarcinoma cells. 1509 77

Activity and expression of fatty acid synthase (FAS), a critical enzyme in the de novo biosynthesis of fatty acids in mammals, is exquisitely sensitive to nutritional regulation of lipogenesis in liver or adipose tissue. Surprisingly, a number of studies have demonstrated hyperactivity and overexpression of FAS (oncogenic antigen-519) in a biologically aggressive subset of human breast carcinomas, suggesting that FAS-dependent neoplastic lipogenesis is unresponsive to nutritional regulation. We have assessed the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) on the enzymatic activity and protein expression of tumor-associated FAS in SK-Br3 human breast cancer cells, an experimental paradigm of FAS-overexpressing tumor cells in which FAS enzyme constitutes up to 28%, by weight, of the cytosolic proteins. Of the omega-3 PUFAs tested, alpha-linolenic acid (ALA) dramatically reduced FAS activity in a dose-dependent manner (up to 61%). omega-3 PUFA docosahexaenoic acid (DHA) demonstrated less marked but still significant inhibitory effects on FAS activity (up to 37%), whereas eicosapentaenoic acid (EPA) was not effective. Of the omega-6 fatty acids tested, gamma-linolenic acid (GLA) was the most effective dose-dependent inhibitor of FAS activity, with a greater than 75% FAS activity reduction. Remarkably, omega-6 PUFAs linoleic acid (LA) and arachidonic acid (ARA), suppressors of both hepatic and adipocytic FAS-dependent lipogenesis, had no significant inhibitory effects on the activity of tumor-associated FAS in SK-Br3 breast cancer cells. Western blotting studies showed that down-regulation of FAS protein expression tightly correlated with previously observed inhibition of FAS activity, suggesting that ALA-, DHA-, and GLA-induced changes in FAS activity resulted from effects at the protein level. We investigated whether the FAS inhibitory effect of GLA and omega-3 PUFAs correlated with a cytotoxic effect related to a peroxidative mechanism. Measurement of cell viability by MTT assay indicated a significant cellular toxicity after ALA and GLA exposures. Furthermore, we observed a significant correlation between the ability of PUFAs to repress FAS and cause cell toxicity. In the presence of anti-oxidants (vitamin E), ALA and GLA dramatically lost their ability to inhibit FAS activity. Interestingly, a combination of ALA and GLA was FAS inhibitory in an additive manner, and this FAS repression was only partially reversible by vitamin E. In examining the molecular mechanisms underlying resistance of breast cancer-associated FAS to normal dietary fatty acid-induced suppression, a dramatic decrease of FAS accumulation was found after exposure of SK-Br3 cells to mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) inhibitor U0126, phosphatidylinositol-3'-kinase (PI-3'K) blocker LY294002, and/or anti-HER-2/neu antibody trastuzumab. Interestingly, a long-term exposure to pharmacological inhibitors of FAS activity cerulenin [(2S,3R) 2,3-epoxy-4-oxo-7E,10E-dodecadienamide] or C75 also resulted in a significant reduction of FAS accumulation. These data indicate that: a) GLA- and omega-3 PUFA-induced repression of tumor-associated FAS may result, at least in part, from a non-specific cytotoxic effect due to peroxidative mechanisms; b) alternatively, GLA and omega-3 PUFAs have a suppressive effect on FAS expression and activity that can result in the accumulation of toxic fluxes of the FAS substrate malonyl-CoA; c) GLA- and/or omega-3 PUFA-induced repression of tumor-associated FAS may represent a novel mechanism of PUFA-induced cytotoxicity clinically useful against breast carcinomas carrying overexpression of FAS enzyme; d) fundamental differences in the ability of FAS gene to respond to normal fatty acid's regulatory actions in lipogenic tissues may account for the observed extremely high levels of FAS in breast carcinoma; and e) FAS overexpression in SK-Br3 breast cancer cells is driven by increases in HER-2/neu signaling, acting in major part through a constitutive downstream art through a constitutive downstream activation of the MAPK ERK1/2 and PI-3'K/AKT transduction cascades.
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PMID:Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis. 1513 77

We designed our experiments to evaluate whether fatty acid synthase (FAS), a lipogenic enzyme linked to tumor virulence in population studies of human cancer, is necessary for the malignant transformation induced by Her-2/neu (erbB-2) oncogene, which is overexpressed not only in invasive breast cancer but also in premalignant atypical duct proliferations and in ductal carcinoma in situ of the breast. To avoid the genetic complexities associated with established breast cancer cell lines, we employed NIH-3T3 mouse fibroblasts engineered to overexpress human Her-2/neu coding sequence. NIH-3T3/Her-2 cells demonstrated a significant upregulation of FAS protein expression, which was dependent on the upstream activation of mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT pathways. Remarkably, pharmacological FAS blockade using the mycotoxin cerulenin or the novel small compound C75 completely suppressed the state of Her-2/neu-induced malignant transformation by inhibiting the ability of NIH-3T3/Her-2 cells to grow under either anchorage-independent (i.e., to form colonies in soft agar) or low-serum monolayer conditions. Moreover, NIH-3T3/Her-2 fibroblasts were up to three times more sensitive to chemical FAS inhibitors relative to untransformed controls as determined by MTT-based cell viability assays. In addition, pharmacological FAS blockade preferentially induced apoptotic cell death of NIH-3T3/Her-2 fibroblasts, as determined by an ELISA for histone-associated DNA fragments and by the terminal deoxynucleotidyltransferase (TdT)-mediated nick end labeling assay (TUNEL). Interestingly, the degree of Her-2/neu oncogene expression in a panel of breast cancer cell lines was predictive of sensitivity to chemical FAS inhibitors-induced cytotoxicity, while low-FAS expressing and chemical FAS inhibitors-resistant MDA-MB-231 breast cancer cells became hypersensitive to FAS blockade when they were engineered to overexpress Her-2/neu. Our observations strongly suggest that inhibition of FAS activity may provide a new molecular avenue for chemotherapeutic prevention and/or treatment of Her-2/neu-related breast carcinomas.
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PMID:Pharmacological inhibition of fatty acid synthase (FAS): a novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her-2/neu (erbB-2) oncogene-induced malignant transformation. 1539 78

Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase orphan receptor Her-2/neu (erbB-2) that has shown therapeutic efficacy against Her-2/neu-overexpressing breast tumors. However, less than 35% of patients with Her-2/neu-overexpressing metastatic breast cancer respond to trastuzumab as a single agent, whereas the remaining cases do not demonstrate tumor regression. Furthermore, the majority of patients who achieve an initial response generally acquire resistance within one year. Therefore, the identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Recent studies in breast cancer cells have revealed a bi-directional connection between Her-2/neu and fatty acid synthase (FAS), a major lipogenic enzyme catalyzing the synthesis of long-chain saturated fatty acids from the 2-carbon donors malonyl-CoA and acetyl-CoA. Her-2/neu overexpression stimulates the FAS promoter and ultimately mediates increased endogenous fatty synthesis, and this Her-2/neu-mediated induction of breast cancer-associated FAS is inhibitable by trastuzumab. On the other hand, chemical FAS inhibitors as well as RNA interference-mediated silencing of FAS gene repress Her-2/neu gene expression at the transcriptional level. Moreover, specific FAS blockade synergistically sensitizes breast cancer cells carrying Her-2/neu-oncogene amplification and/or overexpression to trastuzumab-induced cell growth inhibition and apoptotic cell death. Strikingly, FAS inhibition synergistically interacts with trastuzumab in Her-2/neu-negative breast cancer cells engineered to overexpress Her-2/neu, thus suggesting that the molecular linkage between FAS activity and functioning of Her-2/neu cannot be explained only on the basis of a transcriptional repression of Her-2/neu gene promoter. Interestingly, while in liver and adipose tissue FAS produces fat from excess carbon consumed as carbohydrates, which is ultimately stored as triglycerides, in epithelial cancer cells, FAS activity is mainly involved in the production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), which point to an active role of FAS in the deregulation of membrane functioning in tumor cells. Importantly, clusters of Her-2/neu and EGFR (erbB-1) co-localize with lipid rafts and the lipid environment in the cell membrane of breast cancer cells profoundly influences their association properties and biological functions. We hypothesize that pharmacological or small interference RNA-induced inhibition of breast cancer-associated FAS will result in major changes in the synthesis of phospholipids which, in turn, should impair a correct cellular localization of Her-2/neu at the cellular membrane of breast cancer cells. In this working model, FAS inhibition could induce a shift in the equilibrium between transport of Her-2/neu to and from the membrane favoring an increased Her-2/neu internalization followed by intracellular degradation, thus enhancing the mechanism of action of the anti-Her-2/neu antibody trastuzumab. Moreover, the inhibition of FAS-driven lipid rafts will also negatively affect EGFR-Her-2/neu cross-talk, an important mechanism of trastuzumab resistance. In summary, the specific blockade of a novel molecular linkage between FAS-regulated membrane composition and functioning of transmembrane growth factor receptors EGFR and Her-2/neu may represent a previously unrecognized therapeutic approach circumventing trastuzumab resistance in breast carcinomas.
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PMID:Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. 1578 Apr 99

The receptor tyrosine kinase ErbB2 (HER-2/neu) is overexpressed in up to 30% of breast cancers and is associated with poor prognosis and an increased likelihood of metastasis especially in node-positive tumors. In this proteomic study, to identify the proteins that are associated with the aggressive phenotype of HER-2/neu-positive breast cancer, tumor cells from both HER-2/neu-positive and -negative tumors were procured by laser capture microdissection. Differentially expressed proteins in the two subsets of tumors were identified by two-dimensional electrophoresis and MALDI-TOF/TOF MS/MS. We found differential expression of several key cell cycle modulators, which were linked with increased proliferation of the HER-2/neu-overexpressing cells. Nine proteins involved in glycolysis (triose-phosphate isomerase (TPI), phosphoglycerate kinase 1 (PGK1), and enolase 1 (ENO1)), lipid synthesis (fatty acid synthase (FASN)), stress-mediated chaperonage (heat shock protein 27 (Hsp27)), and antioxidant and detoxification pathways (haptoglobin, aldo-keto reductase (AKR), glyoxalase I (GLO), and prolyl-4-hydrolase beta-isoform (P4HB)) were found to be up-regulated in HER-2/neu-positive breast tumors. HER-2/neu-dependent differential expression of PGK1, FASN, Hsp27, and GLO was further validated in four breast cancer cell lines and 12 breast tumors by immunoblotting and confirmed by partially switching off the HER-2/neu signaling in the high HER-2/neu-expressing SKBr3 cell line with Herceptin treatment. Statistical correlations of these protein expressions with HER-2/neu status were further verified by immunohistochemistry on a tissue microarray comprising 97 breast tumors. Our findings suggest that HER-2/neu signaling may result, directly or indirectly, in enhanced activation of various metabolic, stress-responsive, antioxidative, and detoxification processes within the breast tumor microenvironment. We hypothesize that these identified changes in the cellular proteome are likely to drive cell proliferation and tissue invasion and that the key cell cycle modulators involved, when uncovered by future research, would serve as naturally useful targets for the development of therapeutic strategies to negate the metastatic potential of HER-2/neu-positive breast tumors.
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PMID:Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer. 1604 8

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

Elucidating the mechanisms underlying resistance to the human epidermal growth factor receptor 2 (HER2)-targeted antibody trastuzumab (Tzb; Herceptin) is a major challenge that is beginning to be addressed. This dilemma is becoming increasingly important as recent studies strongly support a role for Tzb in the adjuvant setting for HER2-overexpressing early-stage breast cancers. We previously reported that pharmacological and RNA interference-induced inhibition of tumor-associated fatty acid synthase (FASN; Oncogenic antigen-519), a key metabolic enzyme catalyzing the synthesis of long-chain saturated fatty acids, drastically down-regulates HER2 expression in human breast cancer cells bearing HER2 gene amplification. Given that FASN blockade was found to suppress HER2 overexpression by attenuating the promoter activity of the HER2 gene, we here envisioned that this mechanism of action may represent a valuable strategy in breast cancers that have progressed while under Tzb. We created a preclinical model of Tzb resistance by continuously growing HER2-overexpressing SKBR3 breast cancer cells in the presence of clinically relevant concentrations of Tzb (20-185 microg/ml Tzb). This pool of Tzb-conditioned SKBR3 cells, which optimally grows now in the presence of 100 microg/ml trastuzumab (SKBR3/Tzb100 cells), exhibited HER2 levels notably higher (approximately 2-fold) than those found in SKBR3 parental cells. Real-time polymerase chain reaction studies showed that up-regulation of HER2 mRNA levels closely correlated with HER2 protein up-regulation in SKBR3/Tzb100 cells, thus suggesting that 'HER2 super-expression' upon acquisition of autoresistance to Tzb resulted, at least in part, from up-regulatory effects in the transcriptional rate of the HER2 gene. SKBR3/Tzb100 cells did not exhibit cross-resistance to C75, a small-compound specifically inhibiting FASN activity. On the contrary, SKBR3/Tzb100 cells showed a remarkably increased sensitivity (approximately 3-fold) to the cytotoxic effects occurring upon C75-induced inhibition of FASN enzymatic activity. Both HER2 mRNA and HER2 protein 'super-expression', which have not been reported in earlier Tzb-resistant breast cancer models, were entirely suppressed following pharmacological blockade of FASN activity. Moreover, while Tzb was still able to reduce HER2 protein expression by approximately 20% in SKBR/Tzb100 cells, C75 and Tzb co-exposure synergistically down-regulated HER2 protein levels by >85%. The nature of the interaction between Tzb and C75 in Tzb-resistant SKBR3/Tzb100 cells was also found to be strongly synergistic when analyzing the extent of apoptotic cell death using ELISA-based detection of histone-associated DNA fragments. In summary, a) the molecular mechanism(s) contributing to Tzb resistance in our SKBR3/Tzb100 model appear to be clearly different to those previously reported as we found important transcriptional up-regulatory transcriptional changes in HER2 gene expression levels relative to parental cells; b) since FASN inhibition acts on HER2 gene expression via reduction of its transcription rate, Tzb-conditioned HER2-overexpressing breast cancer cells not only retain but further gain sensitivity to FASN inhibition; and c) transcriptional suppression of HER2 expression using FASN blockers may represent a new molecular strategy in the management of Tzb-resistant breast cancer disease.
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PMID:Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by transcriptionally inhibiting 'HER2 super-expression' occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells. 1778 7

The oncoprotein ErbB2 (HER-2/neu) is a tyrosine kinase cell surface receptor overexpressed in several human malignancies, including oral squamous cell carcinoma (OSCC). ErbB2 was recently shown to regulate the expression of fatty acid synthase (FAS), a multifunctional enzyme complex responsible for the de novo biosynthesis of saturated fatty acids. Here we evaluated the relationship between the immunohistochemical expression of ErbB2, FAS, and Ki-67 with the clinicopathologic characteristics of tongue squamous cell carcinoma (SCC). One hundred and two patients with tongue SCC treated from 1990 to 1995 were studied. Clinical and treatment data were obtained from the medical records and histopathological features revised. Paraffin-embedded tissues were submitted to standard immunohistochemical reactions for ErbB2, FAS and Ki-67. A strong positive correlation between ErbB2 labeling at the cell membrane and FAS expression was found in the tongue SCC samples (p<0.0001). The intracytoplasmatic expression of ErbB2 as well as Ki-67 nuclear staining were significantly associated with a high risk of recurrence by predicting both disease free survival (log-rank test, p=0.0096 and p=0.0047, respectively) and overall survival (log-rank test, p=0.0029 and p=0.0001, respectively). Taken together, our results suggest that the immunolocalization of ErbB2 at the cell surface of malignant oral keratinocytes is linked to FAS expression whereas the intracytoplasmatic ErbB2 or Ki-67 staining predict high risk of recurrence of tongue SCC.
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PMID:ErbB2 and fatty acid synthase (FAS) expression in 102 squamous cell carcinomas of the tongue: correlation with clinical outcomes. 1782 1