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.
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.
We conclude that regulation of FAS expression in breast cancer is achieved through modulation of SREBP-1c, similar to the regulation in liver and adipose tissue, although the upstream regulation of liopgenesis differs in these tissues.
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.
To the best of our knowledge this is the first study demonstrating that FAS is playing an active role in HER -2/ neu -induced breast cancer chemotherapy resistance.
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.
When we characterized signaling molecules participating in the cellular events following orlistat-induced inhibition of FAS activity and preceded inhibition of breast cancer cell proliferation, a dramatic down-regulation of Her2/neu-coded p185(Her2/neu) oncoprotein was found in orlistat-treated SK-Br3 cells (>90% reduction).
Consistent with these results, a significant inverse correlation was observed in the expression of FAS and BNIP3 in clinical samples of human breast cancer.
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.
Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner.
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.
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 summary, a) the molecular mechanism(s) contributing to Tzb resistance in our SKBR3/Tzb100 model appear to be clearly different to those previously reported as we found important transcriptional up-regulatory transcriptional changes in HER2 gene expression levels relative to parental cells; b) since FASN inhibition acts on HER2 gene expression via reduction of its transcription rate, Tzb-conditioned HER2-overexpressing breast cancer cells not only retain but further gain sensitivity to FASN inhibition; and c) transcriptional suppression of HER2 expression using FASN blockers may represent a new molecular strategy in the management of Tzb-resistant breast cancer disease.
Poly(A) tail assays showed that FAS mRNA species from 184A1 cells tended to be longer than those of breast cancer cell lines (500-1500 nt versus 500-800 nt, respectively).
The results show that the expression of FAS varies in the three breast cancer cell lines examined (respectively, SK-Br3>MCF-7>MDA-MB-231), but FAS promoter can initiate relative high transcriptional activities in all three kinds of cancer cells while little in normal fibroblast cells.
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.
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.
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 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).
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.