Free fatty acids enhance breast cancer cell migration through plasminogen activator inhibitor-1 and SMAD4 (original) (raw)
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Medical oncology (Northwood, London, England), 2017
An increased risk of developing breast cancer has been associated with high levels of dietary fat intake. Linoleic acid (LA) is an essential fatty acid and the major ω-6 polyunsaturated fatty acid in occidental diets, which is able to induce inappropriate inflammatory responses that contribute to several chronic diseases including cancer. In breast cancer cells, LA induces migration. However, the signal transduction pathways that mediate migration and whether LA induces invasion in MDA-MB-231 breast cancer cells have not been studied in detail. We demonstrate here that LA induces Akt2 activation, invasion, an increase in NFκB-DNA binding activity, miR34a upregulation and miR9 downregulation in MDA-MB-231 cells. Moreover, Akt2 activation requires EGFR and PI3K activity, whereas migration and invasion are dependent on FFAR4, EGFR and PI3K/Akt activity. Our findings demonstrate, for the first time, that LA induces migration and invasion through an EGFR-/PI3K-/Akt-dependent pathway in M...
Molecular and cellular biochemistry, 2017
Epidemiological studies strongly suggest an association between high levels of dietary fat intake and an increased risk of developing breast cancer. Linoleic acid (LA) is an essential omega-6 PUFA and the major fatty acid in occidental diets. In breast cancer cells, LA induces expression of plasminogen activator inhibitor-1, proliferation, migration, and invasion. Fascin is an actin crosslinker globular protein that generates actin bundles made of parallel actin filaments, which mediate formation and stability of microspikes, stress fibers, membrane ruffles, and filopodia. However, the role of fascin in migration and invasion induced by LA in MDA-MB-231 breast cancer cells remains to be studied. We demonstrate here that LA induces an increase of fascin expression in MDA-MB-231 and MCF12A mammary epithelial cells. Particularly, LA induces the formation of filopodia and lamellipodia and the localization of fascin in these actin structures in MDA-MB-231 breast cancer cells. However, LA...
Linoleic acid induces an increased response to insulin in MDA-MB-231 breast cancer cells
Journal of cellular biochemistry, 2018
Epidemiological studies and animal models suggest a link between high levels of dietary fat intake and an increased risk of developing breast cancer. Hyperinsulinemia is a feature of obesity, diabetes, and metabolic syndrome that is associated with an increased breast cancer risk. Insulin is a hormone involved in metabolic regulation of carbohydrate. However, it is also a growth factor that mediates proliferation and migration. Linoleic acid (LA) is a fatty acid that induces migration and invasion in breast cancer cells. In the present study, we demonstrate, for the first time, that treatment with LA increases IR and IGF1R expression through a Free Fatty Acid Receptor 4 (FFAR4)-, lipooxygenases (LOXs)- and SRC-dependent pathway in MDA-MB-231 breast cancer cells, and similarly induces an increase of IR expression in MCF-7 breast cancer cells. In addition, insulin induces tyrosine phosphorylation of IR/IGF1R and migration in MDA-MB-231 cells pretreated with LA, whereas it augments the...
Cellular Oncology, 2013
Background Epidemiological studies and animal models suggest a link between high levels of dietary fat intake and an increased risk of developing breast cancer. Particularly, free fatty acids (FFAs) are involved in several processes, including proliferation, migration and invasion, in breast cancer cells. Linoleic acid (LA) is a dietary n-6 polyunsaturated fatty acid that is known to induce proliferation and invasion in breast cancer cells. So far, however, the contribution of LA to focal adhesion kinase (FAK) activation and cell migration in breast cancer cells has not been studied. Results Here, we show that LA promotes FAK and Src activation, as well as cell migration, in MDA-MB-231 breast cancer cells. FAK activation and cell migration require Src, Gi/Go, COX-2 and LOXs activities, whereas both are independent of Δ6 desaturase activity. In addition, we show that cell migration requires FAK activity, whereas FAK activation requires Src activity, thus suggesting a reciprocal catalytic activation mechanism of FAK and Src. Conclusions In summary, our findings show that LA induces FAK activation and cell migration in MDA-MB-231 breast cancer cells.
Endocrine Connections, 2019
Free fatty acids (FFAs) are an energy source, and induce activation of signal transduction pathways that mediate several biological processes. In breast cancer cells, oleic acid (OA) induces proliferation, matrix metalloproteinase-9 (MMP-9) secretion, migration and invasion. However, the signal transduction pathways that mediate migration and invasion induced by OA in breast cancer cells have not been studied in detail. We demonstrate here that FFAR1 and FFAR4 mediate migration induced by OA in MDA-MB-231 and MCF-7 breast cancer cells. Moreover, OA induces migration, invasion, AKT1 and AKT2 activation, 12-LOX secretion and an increase of NFκB-DNA binding activity in breast cancer cells. Cell migration requires FFAR1, FFAR4, EGFR, AKT and PI3K activity, whereas invasion is mediated though a PI3K/Akt-dependent pathway. Furthermore, OA promotes relocalization of paxillin to focal contacts and it requires PI3K and EGFR activity, whereas NFκB-DNA binding activity requires PI3K and AKT ac...
Basic aspects of tumor cell fatty acid-regulated signaling and transcription factors
Cancer and Metastasis Reviews, 2011
This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids (PUFAs) of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases (LOXs), cyclooxygenases (COXs), and cytochrome P-450 (CYP-450), seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator-activated receptors (PPARs) or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C [PKC]) and other transcription factors (nuclear factor kappa B [NFκB] and sterol regulatory element binding protein [SREBP]). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer, and provide insight into the development of new therapeutic strategies for a better management of whole-body lipid metabolism.
Linoleic acid induces an EMT-like process in mammary epithelial cells MCF10A
International Journal of Biochemistry & Cell Biology, 2011
Epidemiological studies and animal models suggest an association between high levels of dietary fat intake and an increased risk of developing breast cancer. Epithelial–mesenchymal-transition (EMT) is a process, by which epithelial cells are transdifferentiated to a mesenchymal state, and it has been implicated in cancer progression, including invasion and metastasis. Linoleic acid (LA) induces proliferation and invasion in breast cancer
Effect of linoleic acid on proliferation and gene expression in the breast cancer cell line T47D
Cancer Letters, 2004
Human and animal studies have linked n-6 polyunsaturated fatty acids with mammary carcinogenesis. We investigated the cellular and molecular effects of linoleic acid on the human breast cancer cell line T47D. Linoleic acid had a stimulatory effect on the growth of T47D cells, associated with an increase in the proportion of cells in the S phase of the cell cycle. Microarray, functional group and quantitative PCR analyses indicate that linoleic acid may affect T47D cell growth by modulation of the estrogen receptor (ERa), the G13a G protein, and p38 MAP kinase gene expression as well genes involved in RNA transcription and cell cycle regulation.
Cancer & metabolism, 2017
Obesity is associated with increased recurrence and reduced survival of breast cancer. Adipocytes constitute a significant component of breast tissue, yet their role in provisioning metabolic substrates to support breast cancer progression is poorly understood. Here, we show that co-culture of breast cancer cells with adipocytes revealed cancer cell-stimulated depletion of adipocyte triacylglycerol. Adipocyte-derived free fatty acids were transferred to breast cancer cells, driving fatty acid metabolism via increased CPT1A and electron transport chain complex protein levels, resulting in increased proliferation and migration. Notably, fatty acid transfer to breast cancer cells was enhanced from "obese" adipocytes, concomitant with increased stimulation of cancer cell proliferation and migration. This adipocyte-stimulated breast cancer cell proliferation was dependent on lipolytic processes since HSL/ATGL knockdown attenuated cancer cell responses. These findings highlight ...