Fatty acid synthase expression and its association with clinico-histopathological features in triple-negative breast cancer

584 Background: Fatty acid synthase (FASN) is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and is associated with poor prognosis. In vitro, FASN overexpression induces drug resistance to DNA damaging agents. Proton pump inhibitors (PPI) selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells. We report the results of a single arm phase II study of high dose omeprazole (OMP) in combination with anthracycline- taxane (AC-T) based neoadjuvant chemotherapy. Methods: Patients (pts) with operable TNBC independent of baseline FASN expression; and no prior PPI use within 12 months were enrolled. Pts began OMP 80 mg PO BID for 4-7 days prior to AC-T; carboplatin was allowed per physician discretion. OMP was continued until surgery. Paired biopsy samples were obtained before and after OMP monotherapy. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive disease in breast or axilla, in pts with baseline FASN expression (FASN+) assessed using immunohistochemistry. Relevant secondary endpoints included pCR in the intent to treat population, change in FASN expression, enzyme activity and downstream target gene expression after OMP monotherapy; safety and limited OMP pharmacokinetics. We targeted a pCR rate of 60% in FASN+ pts (null pCR ~ 40%) with 80% power and alpha of 0.10. Results: A total of 42 pts were recruited from 5 US sites. Median age was 51y (28-72). Most pts had >cT2 (33, 79%) and ≥N1 (22, 52%) disease. 14 (33%) were African American. FASN expression prior to AC-T was identified in 28 (85%) samples available for analysis. The pCR rate was 71.4% (95% CI 51.3 to 86.8) in FASN+ pts and 71.8 %( 95% CI 55.1 to 85.0) in all enrolled pts. Fifteen pts (36%) received carboplatin with AC-T; pCR in this subset was 73%. Peak OMP concentration was significantly higher than IC50 observed during preclinical testing; FASN positivity significantly decreased with OMP monotherapy from 0.53(SD 0.25) at baseline to 0.38(SD 0.30; p = 0.02). OMP was well tolerated with no known grade (G) 3 or 4 toxicities. Chemotherapy toxicity was similar to prior studies using AC-T with G3 or 4 neutropenia (19%), febrile neutropenia (7%) and peripheral neuropathy (7%) being the most common. Conclusions: Consistent with previous studies, FASN is frequently expressed in early stage TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of high dose OMP to neoadjuvant AC-T yields a promising pCR rate without adding toxicity. Funded by the Breast Cancer Research Foundation. Clinical trial information: NCT02595372 .

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Abstract P4-09-11: Fatty Acid Synthase (FASN) expression in Triple-Negative Breast Cancer

10.1158/0008-5472.sabcs12-p4-09-11 ◽

2012 ◽

Cited By ~ 2

Author(s):

G Viñas ◽

G Oliveras ◽

F Perez-Bueno ◽

A Giro ◽

A Blancafort ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Triple Negative Breast Cancer ◽

Fatty Acid Synthase ◽

Triple Negative

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Metformin-Induced Killing of Triple-Negative Breast Cancer Cells Is Mediated by Reduction in Fatty Acid Synthase via miRNA-193b

Hormones and Cancer ◽

10.1007/s12672-014-0188-8 ◽

2014 ◽

Vol 5 (6) ◽

pp. 374-389 ◽

Cited By ~ 48

Author(s):

Reema S. Wahdan-Alaswad ◽

Dawn R. Cochrane ◽

Nicole S. Spoelstra ◽

Erin N. Howe ◽

Susan M. Edgerton ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Fatty Acid Synthase ◽

Triple Negative

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(−)-Epigallocatechin 3-Gallate Synthetic Analogues Inhibit Fatty Acid Synthase and Show Anticancer Activity in Triple Negative Breast Cancer

Molecules ◽

10.3390/molecules23051160 ◽

2018 ◽

Vol 23 (5) ◽

pp. 1160 ◽

Cited By ~ 11

Author(s):

Joan Crous-Masó ◽

Sònia Palomeras ◽

Joana Relat ◽

Cristina Camó ◽

Úrsula Martínez-Garza ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Anticancer Activity ◽

Triple Negative Breast Cancer ◽

Fatty Acid Synthase ◽

Triple Negative ◽

Synthetic Analogues

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Inhibition of USP2 Induces Apoptosis through Down Regulation of Fatty Acid Synthase and Cyclin D1 in Triple Negative Breast Cancer

Current Proteomics ◽

10.2174/1570164617666191008093522 ◽

2020 ◽

Vol 17 (5) ◽

pp. 425-432

Author(s):

Nida Syed ◽

Amber Ilyas ◽

Farha Idrees ◽

Zarina ◽

Zehra Hashim

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Fatty Acid ◽

Early Detection ◽

Cyclin D1 ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cell Line ◽

Fatty Acid Synthase ◽

Triple Negative ◽

Cancer Cell Line

Background: Breast cancer is the most occurring cancer in women with high incidence rates both in developed and developing countries. Among different types of breast cancers, Triple Negative Breast Cancer (TNBC) is the most aggressive type as it lacks receptors of Estrogen, Progesterone and Human Epidermal Growth Factor Receptor 2, common diagnostic biomarkers for the disease. Since early detection of TNBC can save thousands of lives, there is a dire need to discover and develop effective and affordable methods for early detection. Different Post Translational Modifications (PTMs) have been proposed as potential biomarker for various clinical conditions. Ubiquitination is a type of PTM involved in the stability and regulation of cellular proteins. Objective: It is hypothesized that reticence of ubiquitination may lead to cell death. Current study focuses on the inhibition of Ubiquitin Specific Protease (USP), USP2 using its inhibitor, ML364 in HTB- 132 triple negative breast cancer cell line to induce cell death. The aim of the current study was to evaluate anticancer property of ML364 that might be a promising novel therapeutic agent for TNBC. Furthermore, current investigations focus on USP2 and their focal stabilizing substrates i.e. Fatty acid Synthase (FAS) and Cyclin D1 could be potential prognostic markers for the disease. Methods: Quantitative PCR of CyclinD1, USP2, MDM2, and Fatty Acid Synthase (FAS) was performed to identify the deubiquitination effect of ML364 in breast cancer cells, which complemented our results with studies on normal and breast cancerous tissue samples. Results: Expression of USP2 and its substrates Cyclin D1and FAS was found to be down regulated in ML364 treated breast cancer cell line whereas higher expression was observed in breast cancer tissue, indicating therapeutic potential of USP2 inhibitor. Conclusion: Our findings suggest that USP2, Cyclin D1 and FAS could be used as prognostic marker and therapeutic target for TNBC.

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