Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty acid synthase is overexpressed in cancer especially in tumors with a poor prognosis. The specific fatty acid synthase inhibitor cerulenin can induce apoptosis in cancer cells. Likewise, phosphatidylinositol 3-kinase (PI3K)/Akt kinase activities are elevated in primary tumors and cancer cell lines. Here, we tested whether inhibition of PI3K/Akt pathway would sensitize cancer cells to cerulenin-induced apoptosis. We show that LY294002, an inhibitor of PI3K, sensitized MDA-MB468 breast cancer cells to cerulenin-induced apoptosis. In MDA-MB468 cells, cerulenin- and LY294002-mediated apoptosis was associated with caspase-3 activation and the release of cytochrome c from mitochondria to cytosol. In addition, we observed additional species of Bak in mitochondria, suggesting a possible Bak activation. Treatment of cells with cerulenin and LY294002 down-regulated the protein levels of X chromosome-linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis 1 (cIAP-1), and Akt, whereas the levels of mitogen-activated protein/extracellular signal-regulated kinase kinase and other antiapoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xl) did not change. Interestingly, the nonspecific caspase inhibitor, z-VAD-FMK, inhibited the down-regulation of Akt, XIAP, and cIAP-1 in cerulenin- and LY294002-treated cells. In conclusion, these studies show that inhibition of PI3K can sensitize cerulenin-induced apoptosis in MBA-MB468 breast cancer cells via activation of caspases, down-regulation of antiapoptotic proteins, such as XIAP, cIAP-1 and Akt, and possibly, activation of Bak in mitochondria.
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PMID:Inhibition of the phosphatidylinositol 3-kinase/Akt pathway sensitizes MDA-MB468 human breast cancer cells to cerulenin-induced apoptosis. 1654 63

Most breast cancers are "lipogenic", defined by high fatty acid synthase (FAS) content and dependence on fatty acid synthesis for growth and survival. S14 (Spot 14; THRSP) is a nuclear protein that activates genes required for fatty acid synthesis. The S14 gene is amplified in approximately 15% of breast cancers, but clinical correlates of its expression were unknown. We analyzed 131 breast cancers by immunohistochemistry for S14 and FAS. Staining was graded 0, 1, or 2+, and scores were correlated with traditional tumor markers, histological features, and outcome. S14 and FAS staining were related to tumor size (p=0.05 for S14, p=0.038 for FAS), but not to stage. S14 but not FAS scores correlated with tumor grade in both DCIS (p=0.003) and invasive cases (p<0.001). Invasive cases (pooled node - and +) with weak S14 staining (n=21) showed no recurrence over 3000 d follow-up, including 10 cases with lymph node involvement, whereas 32% of 67 strongly-staining tumors recurred (log rank p<0.0001). S14 scores did not cosegregate with sex steroid receptors, Her2/neu, or cyclin D1. Low level S14 expression is associated with prolonged disease-free survival in invasive cases, including those with nodal metastasis. High-level expression of S14 identifies a subset of high-risk breast cancers that is not specified by analysis of sex steroid receptors, Her2/neu, or cyclin D1, and provides a molecular correlate to histologic features that predict recurrence.
Breast Cancer Res Treat 2006 Jul
PMID:Expression of "Spot 14" (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker. 1655 28

Cancer cells frequently exhibit a significant increase in overexpression and activity of fatty acid synthase (FASN). Elevated FASN pathway activity also occurs in prostate cancer, the second leading cause of cancer-related death in men in the United States. Studies show that genes associated with an increase in protein expression, such as HER2/neu in breast cancer, are associated with an increase in gene copy number as well as an increase in transcription. In the present study, we evaluated whether FASN follows a similar paradigm in prostate cancer. To date, elevated FASN expression in prostate cancer has not been correlated with gene copy number alterations. Using immunohistochemistry and fluorescence in situ hybridization analysis in paraffin-embedded tissue microarrays, we observed gene copy gain in 24% of all prostate adenocarcinoma specimens examined with concurrent increased FASN protein expression. Immunohistochemistry alone showed 59% of prostate cancer specimens in the same tissue microarray with high FASN expression. Increased FASN gene was observed in 53% of all prostate tissues expressing elevated FASN protein levels and in 2 of 5 prostate tumor cell lines tested. These findings suggest that FASN gene copy number increases may be involved in the resultant increase in FASN protein expression observed in prostatic disease.
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PMID:Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. 1656 13

Fatty acid metabolism in the hypothalamus has recently been shown to regulate feeding. The selective estrogen receptor modulator tamoxifen (TMX) exerts a potent anorectic effect. Here, we show that the anorectic effect of TMX is associated with the accumulation of malonyl-CoA in the hypothalamus and inhibition of fatty acid synthase (FAS) expression specifically in the ventromedial nucleus of the hypothalamus (VMN). Furthermore, we demonstrate that FAS mRNA expression is physiologically regulated by fasting and refeeding in the VMN but not in other hypothalamic nuclei. Thus, the VMN appears to be the hypothalamic site where regulation of FAS and feeding converge. Supporting the potential clinical relevance of these observations, reanalysis of a primary breast cancer prevention study showed that obese women treated with TMX gained significantly less body weight over a 6-year period than obese women given placebo. The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior.
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PMID:Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. 1664 89

Activation of de novo fatty acid synthesis is a characteristic feature of cancer cells. We have recently described an interaction between acetyl-CoA carboxylase alpha (ACCalpha), a key enzyme in fatty acid synthesis, and BRCA1, which indicates a possible connection between lipid synthesis and genetic factors involved in susceptibility to breast and ovarian cancers. For this reason, we explored the role of ACCalpha in breast cancer cell survival using an RNA interference (RNAi) approach. We show that specific silencing of either the ACCalpha or the fatty acid synthase (FAS) genes in cancer cells results in a major decrease in palmitic acid synthesis. Depletion of the cellular pool of palmitic acid is associated with induction of apoptosis concomitant with the formation of reactive oxygen species (ROS) and mitochondrial impairment. Expression of a small interfering RNA (siRNA)-resistant form of ACCalpha mRNA prevented the effect of ACCalpha-RNAi but failed to prevent the effect of FAS gene silencing. Furthermore, supplementation of the culture medium with palmitate or with the antioxidant vitamin E resulted in the complete rescue of cells from both ACCalpha and FAS siRNA-induced apoptosis. Finally, human mammary epithelial cells are resistant to RNAi against either ACCalpha or FAS. These data confirm the importance of lipogenesis in cancer cell survival and indicate that this pathway represents a key target for antineoplastic therapy that, however, might require specific dietary recommendation for full efficacy.
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PMID:Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. 1670 54

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

Progestins increase the risk of breast cancer in the hormone therapy of menopause, and progesterone receptor-induced fatty acid synthase (FAS) is a potential therapeutical target of breast cancer. In a first attempt to specify in which lesions at risk of breast cancer progestins might be acting, we have compared the progesterone receptor (PR) and FAS expression in preinvasive breast lesions and in adjacent "normal" mammary glands. We used archive paraffin-embedded tissues from 116 patients, with 164 lesions of increasing histological risk from nonproliferative "benign" breast disease (BBD) to in situ breast carcinomas. Immunostaining using our FAS antibody and a PR antibody from Dako was quantified as continuous variables by computer-assisted image analysis. FAS level increased (p < 10(-3) by the Kruskall-Wallis test) in all lesions, starting from nonproliferative BBD, and was maximal in in situ carcinoma. The % of PR-positive cells increased from nonproliferative BBD and was higher in proliferative atypia (p < 10(-3)). It was very low in high-grade DCIS corresponding to a likely different carcinogenesis pathway. There was a trend for a positive correlation between FAS and PR in normal glands. However, the 2 markers increased independently in BBD and were negatively correlated in in situ carcinomas. FAS and PR were positively correlated with Ki67 in BBD. The increased PR level in premalignant steps of mammary carcinogenesis suggests an early increased responsiveness to progestins. The increased FAS expression, in lesions parallel to their increased breast cancer risk, suggests further studies to develop new markers of high-risk lesions and to prevent breast cancer.
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PMID:Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis. 1704 16

Tumor-associated fatty acid synthase (FAS) is implicated in tumorigenesis and connected to HER2 (human epidermal growth factor receptor 2) by systemic analyses. Suppression of FAS in cancer cells may lead to growth inhibition and cell apoptosis. Our previous study demonstrated that (-)-epigallocatechin 3-gallate (EGCG), the green tea catechin, could down-regulate FAS expression by suppressing EGFR (epidermal growth factor receptor) signaling and downstream phosphatidylinositol 3-kinase (PI3K)/Akt activation in the MCF-7 breast cancer cell line. Herein, we examined the effects of EGCG on FAS expression modulated by another member of the erbB family, that is, HER2 or HER3. We identified that heregulin-beta1 (HRG-beta1), a HER3 ligand, stimulated dose-dependent FAS expression in breast cancer cell lines MCF-7 and AU565, but not MDA-MB-453. The time-dependent increase in FAS expression after HRG-beta1 stimulation was also observed in MCF-7 cells, and this up-regulation was de novo RNA synthesis dependent. Treatment of MCF-7 cells with EGCG markedly inhibited HRG-beta1-dependent induction of mRNA and protein of FAS. EGCG also decreased the phosphorylation of Akt and extracellular signal-regulated kinase 1/2 that were demonstrated as selected downstream HRG-beta1-responsive kinases required for FAS expression using dominant-negative Akt, PI3K inhibitors (LY294002 and wortmannin), or MEK inhibitor (PD98059). FAS induction by HRG-beta1 was also blocked by AG825, a selective HER2 inhibitor, and by genistein, a selective tyrosine kinase inhibitor, indicating the formation of a heterodimer between HER2 and HER3, and their tyrosine kinase activities are essential for HRG-beta1-mediated elevation of FAS. Additionally, growth inhibition of HRG-beta1-treated cells was parallel to suppression of FAS by EGCG. Taken together, these findings extend our previous study to indicate that EGCG may be useful in the chemoprevention of breast carcinoma in which FAS overexpression results from HER2 or/and HER3 signaling.
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PMID:Tea polyphenol (-)-epigallocatechin 3-gallate suppresses heregulin-beta1-induced fatty acid synthase expression in human breast cancer cells by inhibiting phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase cascade signaling. 1753 58

Progesterone regulates the proliferation and differentiation of normal mammary epithelium. In breast cancer cells, progesterone and its synthetic analogs, progestins, induce long-term growth inhibition and differentiation. However, the mechanisms responsible are not fully understood. When T-47D breast cancer cells were treated with the synthetic progestin ORG 2058 (16alpha-ethoxy-21-hydroxy-19-norpregn-4-en-3,20-dione), all isoforms of Wilms' tumor protein 1 (Wt1) mRNA and protein were rapidly downregulated. We reasoned that the decrease in Wt1 levels may contribute to the long-term antiproliferative and differentiative effects of progestins as proliferation and differentiation are known end points of Wt1 action. Consistent with this idea, Wt1 small interfering RNA led to a decrease in S phase and cyclin D1 levels, and increased Oil-Red-O staining, indicating increased lipogenesis. Conversely, overexpression of Wt1 attenuated the decrease in S phase induced by ORG 2058 at 48-96 h. This was accompanied by the sustained expression of cyclin D1 despite progestin treatment, and increased levels of retinoblastoma (Rb) phosphorylation at sites targeted by cyclin D1-Cdk4 (Ser249/Thr252). Wt1 overexpression also attenuated the ORG 2058-mediated increase in fatty acid synthase levels and reduced lipogenesis. Thus, Wt1 downregulation was sufficient to mimic the effects of progestin and was necessary for complete progestin-mediated proliferative arrest and subsequent differentiation. Furthermore, Wt1 overexpression modulated the effects of progestins but not anti-estrogens or androgens. These results indicate that Wt1 is an important early target of progestins that regulates both proliferation and differentiation in breast cancer cells.
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PMID:Wilms' tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation. 1759 43

Expression of the HER2 oncogene is increased in approximately 30% of human breast carcinomas and is closely correlated with the expression of fatty acid synthase (FASN). In the present study, we determined the mechanism by which FASN and acetyl-CoA carboxylase alpha (ACCalpha) could be induced by HER2 overexpression. SK-BR-3 and BT-474 cells, breast cancer cells that overexpress HER2, expressed higher levels of FASN and ACCalpha compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACCalpha in BT474 cells were not mediated by the activation of SREBP-1. Exogenous HER2 expression in MDA-MB-231 cells induced the expression of FASN and ACCalpha, and the HER2-mediated increase in ACCalpha and FASN was inhibited by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACCalpha. On the other hand, FASN and ACCalpha were reduced in BT-474 cells by a blockade of the mTOR signaling pathway. These changes observed in their protein levels were not accompanied by changes in their mRNA levels. The 5'- and 3'-untranslated regions of both FASN and ACCalpha mRNAs were involved in selective translational induction that was mediated by mTOR signal transduction. These results strongly suggest that the major mechanism of HER2-mediated induction of FASN and ACCalpha in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.
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PMID:Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. 1763


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