The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival

G Protein-coupled Estrogen Receptor Mediates the Up-regulation of Fatty Acid Synthase Induced by 17β-Estradiol in Cancer Cells and Cancer-associated Fibroblasts

“…In MCF-7 breast cancer cells, FASN expression was influenced by E2 and progestins through the sterol receptor element binding protein 1 (SREBP-1) pathway as also observed in prostate cancer cells by androgens (52). In these studies, the activation of steroid receptors mediated the up-regulation of FASN as the antiandrogen bicalutamide, the antiprogestin mifepristone (RU486), and the antiestrogens 4-hydroxytamoxifen and faslodex (ICI 182780) inhibited the FASN response to the cognate ligands of hormone receptors (30,36,(53)(54)(55)(56). Nevertheless, the inhibition of MAPK and PI3K signaling pathways abolished FASN induction by steroids (32,51), suggesting that complex transduction mechanisms may contribute to the regulation of FASN expression.…”

“…Induced by E2 and G-1-In diverse cancer cell types, FASN activity stimulates the synthesis of lipids, which are necessary for the initiation of signaling pathways involved in cell proliferation and migration (30,32,36). Performing proliferation assays in SkBr3, LoVo, and HepG2 cells, and CAFs, the increased cell growth observed upon exposure to E2 and G-1 was abolished using the inhibitor of the FASN activity named cerulenin [(2S,3R)-2,3-epoxi-4-oxo-7,10-dodecadienoxylamide] (Fig.…”

“…One main metabolic change in cancer cells is represented by an altered lipogenic pathway such as an increased synthesis of fatty acids, which are important substrates in the energy production, building blocks of cellular membranes, intracellular second messengers, and anchorage for membrane proteins (29). Free fatty acids derive from both the diet and de novo synthesis, which is catalyzed in lipogenic tissues by fatty acid synthase (FASN) that is able to generate palmitate from malonyl-CoA and acetyl-CoA in the presence of NADPH (29,30). In normal cells, FASN expression is relatively low and occurs in liver and adipose tissues mainly through nutritional signals; conversely, in cancer cells, FASN levels are elevated and independent of nutritional signals (31).…”

Lysophosphatidic Acid Activates Lipogenic Pathways and de Novo Lipid Synthesis in Ovarian Cancer Cells

“…In particular, FAS, originally recognized as a tumor-specific antigen present in serum of cancer patients (34), is overexpressed in a variety of human malignancies. However, the cellular mechanisms by which lipogenic enzymes are up-regulated in cancer cells remain poorly understood except for a few studies suggesting that steroid hormones and Her family ligands could increase FAS expression via the PI3K or MAPK pathways (52)(53)(54)(55).…”

Citrate transport and metabolism in mammalian cells

“…When iron is available, it facilitates the formation of iron-sulphur clusters and IRP acquires enzymatic activity. (55) FAS is highly over-expressed in several different cancers, including those of prostate, (56) breast, (57) ovary, (58) stomach, (59) colon (60) and brain. (61) c-ICD is also upregulated in cancers, including pancreas, (62) colon (63) and gastrointestinal tract.…”