Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism.
One of the HER2-regulated genes discovered was fatty acid synthase (FAS), which has been shown to be overexpressed in breast cancer as well as other cancers.
Clinicopathological assessment of the functional relationship between the HER2 oncogene and tumor-associated fatty acid synthase (FASN) is largely precluded because immunohistochemical and/or mRNA studies should be performed in biopsies from breast cancer patients.
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.
G28UCM inhibits fatty acid synthase (FASN) activity and the growth of breast carcinoma xenografts in vivo, and is active in cells with acquired resistance to anti-HER2 drugs, which make it a candidate for further pre-clinical development.
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).
Consistent with these results, a significant inverse correlation was observed in the expression of FAS and BNIP3 in clinical samples of human breast cancer.
Here, we explore the immunohistochemical expression of FAS and human acetyl-CoA carboxylase (HACC), the rate-limiting enzyme in fatty acid synthesis, in breast cancer progression from histologically normal breast through the development of in situ duct and lobular carcinoma to infiltrating carcinoma.
Expert opinion: With the recent demonstration of target engagement and early signs of clinical activity with the first orally available, selective, potent and reversible FASN inhibitor, we can expect Big pharma to revitalize their interest in lipogenic enzymes as well-credentialed targets for oncology drug development in breast cancer.
The effects of LCA on breast cancer-derived MCF-7 and MDA-MB-231 cells were studied using MTT viability assays, Annexin-FITC and Akt phosphorylation assays to evaluate anti-proliferative and pro-apoptotic properties, qRT-PCR and Western blotting assays to assess the expression of the bile acid receptor TGR5 and the estrogen receptor ERα, and genes and proteins involved in apoptosis (Bax, Bcl-2, p53) and lipogenesis (SREBP-1c, FASN, ACACA).
SIGNIFICANCE STATEMENT: An iterative process of synthesis and biological testing was used to identify a novel thioesterase domain FASN inhibitor that has drug-like properties, is more cytotoxic to breast cancer cells than the widely used tetrahydro-4-methylene-2<i>S</i>-octyl-5-oxo-3<i>R</i>-furancarboxylic acid, and has negligible effects on the growth and proliferation of noncancerous mammary epithelial cells.
We investigated whether the genetic variability of the genes encoding for ChREBP, SREBP and FAS (respectively, MLXIPL, SREBF1 and FASN) is related to breast cancer risk and body-mass index (BMI) by studying 1,294 breast cancer cases and 2,452 controls from the European Prospective Investigation on Cancer (EPIC).
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.
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.
Together with previous findings of FASN as a poor prognosis marker for breast cancer patients, our results suggest that FASN overexpression is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy.
Activation of prolyl hydroxylase-2 for stabilization of mitochondrial stress along with simultaneous downregulation of HIF-1α/FASN in ER + breast cancer subtype.
We found that FAS was significantly up-regulated by hypoxia, which was also accompanied by reactive oxygen species (ROS) generation in human breast cancer cell lines.
Although it was shown that FASN inhibition induced apoptosis by enhancing the cytotoxicity of certain drugs in breast cancer, its role in regulating the chemosensitivity of different types of breast cancer cells to CDDP-induced apoptosis is not established yet.
These results demonstrate that C75-induced cytotoxic damage to breast cancer cells is closely dependent on its ability to inhibit FAS-catalyzed endogenous fatty acid biogenesis, thus ruling out a significant direct effect of C75 on DNA.
Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells.