Fatty Acid Synthase Is a Potential Therapeutic Target in Estrogen Receptor-/Progesterone Receptor-Positive Endometrioid Endometrial Cancer

Rahman, Mohammed Tanjimur; Nakayama, Kentaro; Ishikawa, Masatoshi; Rahman, Munmun; Katagiri, Hiroshi; Katagiri, Atsuko; Ishibashi, Tatsuro; Iida, Kouji; Miyazaki, Kohji

doi:10.1159/000342967

Cited by 26 publications

(12 citation statements)

References 51 publications

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“…FASN is regulated by estrogen in ER-positive breast cancer cells; estrogen stimulates FASN expression. FASN expression is part of the E2-mediatedcellular response that leads to the proliferation of hormone-dependent carcinoma cells[19]–[21]. Inhibiting FASN dramatically augments E2-stimulated, ER-driven transcriptional activity, synergistically enhances the E2-mediated down-regulation of ER expression and impairs E2-induced nuclear accumulation of ER.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibiting FASN dramatically augments E2-stimulated, ER-driven transcriptional activity, synergistically enhances the E2-mediated down-regulation of ER expression and impairs E2-induced nuclear accumulation of ER. Furthermore, inhibiting FASN induces antitumor activity by acting as a SERM in ER-positive breast cancer cells[19]–[21].Therefore, FASN is most likely the downstream effector underlying ER/HER2 crosstalk in dual-positive breast cancer, but the signaling pathway that is involved remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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The mTOR Inhibitor Rapamycin Synergizes with a Fatty Acid Synthase Inhibitor to Induce Cytotoxicity in ER/HER2-Positive Breast Cancer Cells

et al. 2014

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Patients with ER/HER2-positive breast cancer have a poor prognosis and are less responsive to selective estrogen receptor modulators; this is presumably due to the crosstalk between ER and HER2. Fatty acid synthase (FASN) is essential for the survival and maintenance of the malignant phenotype of breast cancer cells. An intimate relationship exists between FASN, ER and HER2. We hypothesized that FASN may be the downstream effector underlying ER/HER2 crosstalk through the PI3K/AKT/mTOR pathway in ER/HER2-positive breast cancer. The present study implicated the PI3K/AKT/mTOR pathway in the regulation of FASN expression in ER/HER2-positive breast cancer cells and demonstrated that rapamycin, an mTOR inhibitor, inhibited FASN expression. Cerulenin, a FASN inhibitor, synergized with rapamycin to induce apoptosis and inhibit cell migration and tumorigenesis in ER/HER2-positive breast cancer cells. Our findings suggest that inhibiting the mTOR-FASN axis is a promising new strategy for treating ER/HER2-positive breast cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mTOR Inhibitor Rapamycin Synergizes with a Fatty Acid Synthase Inhibitor to Induce Cytotoxicity in ER/HER2-Positive Breast Cancer Cells

et al. 2014

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“…FASN has also not previously been reported as a diagnostic biomarker for EOC, but it is known to be overexpressed in many cancers and has been proposed as a therapeutic target in ovarian cancer and other malignancies . FASN expression is positively correlated with ER and PR expression in endometrial cancer and has been implicated in ERBB receptor signaling in ovarian cancer . FASN is involved in the synthesis of long chain saturated fatty acids, which are components of lipid rafts on the cell membrane that form sites of transmembrane protein localization.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three‐dimensional genetic models of ovarian carcinogenesis

Lawrenson

Mhawech‐Fauceglia

Worthington

et al. 2015

Intl Journal of Cancer

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Epithelial ovarian cancer (EOC) is still considered the most lethal gynecological malignancy and improved early detection of ovarian cancer is crucial to improving patient prognoses. To address this need, we tested whether candidate EOC biomarkers can be identified using three-dimensional (3D) in vitro models. We quantified changes in the abundance of secreted proteins in a 3D genetic model of early-stage EOC, generated by expressing CMYC and KRAS G12V in TERT-immortalized normal ovarian epithelial cells. Cellular proteins were labeled in live cells using stable isotopic amino acid analogues, and secreted proteins identified and quantified using liquid chromatography-tandem mass spectrometry. Thirty-seven and 55 proteins were differentially expressed by CMYC and CMYC1KRAS G12V expressing cells respectively (p < 0.05; >2-fold). We evaluated expression of the top candidate biomarkers in~210 primary EOCs: CHI3L1 and FKBP4 are both expressed by >96% of primary EOCs, and FASN and API5 are expressed by 86 and 75% of cases. High expression of CHI3L1 and FKBP4 was associated with worse patient survival (p 5 0.042 and p 5 0.002, respectively). Expression of LGALS3BP was positively associated with recurrence (p 5 0.0001) and suboptimal debulking (p 5 0.018) suggesting that these proteins may be novel prognostic biomarkers. Furthermore, within early stage tumours (I/II), high expression of API5, CHI3L1 and FASN was associated with high tumour grade (p 5 3 3 10 24 , p 5 0.016, p 5 0.010, respectively). We show in vitro cell biology models of early-stage cancer development can be used to identify novel candidate biomarkers for disease, and report the identification of proteins that represent novel potential candidate diagnostic and prognostic biomarkers for this highly lethal disease.Despite recent advances in surgery and chemotherapy, epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, mainly due to the absence of specific symptoms and a lack of effective screening tools. The majority of patients present with advanced stage disease where the 5-year survival rate is only 27%. For advanced stage tumours, recurrence rates are over 60%, and 20% of these patients respond poorly to platinum-based chemotherapy. Therefore, detecting patients with early EOC continues to be an urgent clinical need and it remains a clinical priority to detect highgrade serous EOC early during disease development.Given the difficulties accessing the ovary for biopsy and the rapid rate at which the most aggressive EOC subtypes progress, the identification of clinical biomarkers detectable in the blood would represent a significant advance for the identification of patients with EOC. Currently the most widely used ovarian cancer biomarker is serum CA125, and this marker is particularly good at detecting disease recurrence. A second marker, HE4, was approved in 2009 for monitoring ovarian cancer progression, and can be elevated

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“…FASN is increased in a variety of human tumors and has been demonstrated to be associated with tumor cell growth, apoptosis and metastasis (28)(29)(30)(31). It has been previously demonstrated that inhibition of FASN through use of pharmacological inhibitors or RNA interference significantly inhibits OS cell growth, migration and invasion in vitro and in vivo (32,33).…”

Section: Discussionmentioning

confidence: 99%

LY294002 inhibits the malignant phenotype of osteosarcoma cells by modulating the phosphatidylinositol 3-kinase/Akt/fatty acid synthase signaling pathway in vitro

Zhou

Zhu

Peng

et al. 2014

Molecular Medicine Reports

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Abstract. Increasing evidence suggests that fatty acid synthase (FASN) is crucial in the carcinogenesis of various types of tumor. In addition, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which is closely associated with cellular metabolism, affects cancer biology. However, whether the malignant phenotype of osteosarcoma (OS) cells is regulated by the PI3K/Akt/FASN signaling pathway and how the PI3K family specific inhibitor, 2-(4-morpholinyl)-8-phenyl-chromone (LY294002) affects the malignant phenotype of OS cells remains to be elucidated. In the present study, U2-OS and MG-63 cells were treated with LY294002 and subsequently western blot analysis was used to examine Akt, p-Akt and FASN protein expression. Additionally, FASN mRNA was detected by reverse transcription quantitative polymerase chain reaction. MTT and fluorescence-activated cell sorting assays were used to assess proliferation and apoptosis. Migration and invasion were investigated using wound healing and transwell invasion assays. The results demonstrated that LY294002 suppressed the PI3K/Akt/FASN signaling pathway. However, the malignant phenotypes of OS cells mentioned above were significantly inhibited. The present results indicated that LY294002 inhibits the malignant phenotype of OS cells via modulation of the PI3K/Akt/FASN signaling pathway in vitro and may be a new therapeutic strategy for the management of OS.

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Fatty Acid Synthase Is a Potential Therapeutic Target in Estrogen Receptor-/Progesterone Receptor-Positive Endometrioid Endometrial Cancer

Cited by 26 publications

References 51 publications

The mTOR Inhibitor Rapamycin Synergizes with a Fatty Acid Synthase Inhibitor to Induce Cytotoxicity in ER/HER2-Positive Breast Cancer Cells

The mTOR Inhibitor Rapamycin Synergizes with a Fatty Acid Synthase Inhibitor to Induce Cytotoxicity in ER/HER2-Positive Breast Cancer Cells

Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three‐dimensional genetic models of ovarian carcinogenesis

LY294002 inhibits the malignant phenotype of osteosarcoma cells by modulating the phosphatidylinositol 3-kinase/Akt/fatty acid synthase signaling pathway in vitro

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