FASN phosphorylation by HER2 plays an important role in breast cancer progression and may be a novel therapeutic target in HER2-overexpressing breast cancer cells.
FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21<sup>WAF1/CIP1</sup> and p27<sup>Kip1</sup>, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E<sub>2</sub>-promoted anchorage-independent growth.
Activation of prolyl hydroxylase-2 for stabilization of mitochondrial stress along with simultaneous downregulation of HIF-1α/FASN in ER + breast cancer subtype.
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.
Among them, 1,3,6-Trihydroxy-7-methyl-9,10-anthracenedione (TMA, compound 6) showed strong inhibitory effect on the expression level on fatty acid synthase in human breast cancer MDA-MB-231 cells.
As a result, curcumin induced human breast cancer MDA-MB-231 cell apoptosis with the half-inhibitory concentration value of 3.63 ± 0.26 µg/ml, and blocked FAS activity, expression and mRNA level in a dose-dependent manner.
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.
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.
Collectively, our findings strongly suggest that the HER2-FASN lipogenic axis delineates a group of breast cancer patients that might benefit from treatment with therapeutic regimens containing FASN inhibitors.
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.
Consistent with these results, a significant inverse correlation was observed in the expression of FAS and BNIP3 in clinical samples of human breast cancer.
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.
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).
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.
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.
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.
Here, we summarize the design and development of G28UCM, the lead-compound of a novel family of synthetic FASN inhibitors, with both in vitro and in vivo activity in a human breast cancer model of FASN(+) and HER2(+) .
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.
Increasing evidences suggest that fatty acid synthase (FAS) plays an important role in the development of human breast cancer, for the expression of FAS is significantly higher in breast cancer cells than in normal cells.