Long Chain Fatty Acyl-CoA Synthetase 4 Is a Biomarker for and Mediator of Hormone Resistance in Human Breast Cancer

Abstract

The purpose of this study was to determine the role of long-chain fatty acyl-CoA synthetase 4 (ACSL4) in breast cancer. Public databases were utilized to analyze the relationship between ACSL4 mRNA expression and the presence of steroid hormone and human epidermal growth factor receptor 2 (HER2) in both breast cancer cell lines and tissue samples. In addition, cell lines were utilized to assess the consequences of either increased or decreased levels of ACSL4 expression. Proliferation, migration, anchorage-independent growth and apoptosis were used as biological end points. Effects on mRNA expression and signal transduction pathways were also monitored. A meta-analysis of public gene expression databases indicated that ACSL4 expression is positively correlated with a unique subtype of triple negative breast cancer (TNBC), characterized by the absence of androgen receptor (AR) and therefore referred to as quadruple negative breast cancer (QNBC). Results of experiments in breast cancer cell lines suggest that simultaneous expression of ACSL4 and a receptor is associated with hormone resistance. Forced expression of ACSL4 in ACSL4-negative, estrogen receptor α (ER)-positive MCF-7 cells resulted in increased growth, invasion and anchorage independent growth, as well as a loss of dependence on estrogen that was accompanied by a reduction in the levels of steroid hormone receptors. Sensitivity to tamoxifen, triacsin C and etoposide was also attenuated. Similarly, when HER2-positive, ACSL4-negative, SKBr3 breast cancer cells were induced to express ACSL4, the proliferation rate increased and the apoptotic effect of lapatinib was reduced. The growth stimulatory effect of ACSL4 expression was also observed in vivo in nude mice when MCF-7 control and ACSL4-expressing cells were utilized to induce tumors. Our data strongly suggest that ACSL4 can serve as both a biomarker for, and mediator of, an aggressive breast cancer phenotype.

Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance

“…A study indicates that the ER expression level is negatively associated with ACSL4 expression through 10 published mRNA array datasets in breast cancer cell lines (26). In addition, ACSL4 is considered a biomarker for breast cancer and is associated with aggressive breast cancer type (27). However, the association between other ACSL isoforms and molecular subtypes of breast cancers is poorly known.…”

Identification of Specific Gene Modules in Mouse Lung Tissue Exposed to Cigarette Smoke

“…And both of them are documented in development of many cancers including lung cancers. UPR was demonstrated that was involved in oncogenic transformation and interaction of oncogene and tumor suppressor gene networks to modulate the lung cancer development (Yadav et al, 2014). Glycolysis pathway has been known for providing the energy for cancer cell growth and as biomarker for pneumonocyte malignant transformation (Sasaki et al, 2012).…”

“…ACSL4 also promote the breast cancer cell proliferation and reduce the cell apoptosis. And ACSL4 was regarded as biomarker and mediator of aggressive breast cancer (Wu et al, 2013). The role of ACSL4 in lung cancer development was not identified yet.…”

Gene Expression Profile and Signaling Pathways in MCF-7 Breast Cancer Cells Mediated by Acyl-Coa Synthetase 4 Overexpression

“…It has been shown that both in breast cancer cell lines and in tumor samples the expression of acyl-CoA synthetase 4 (ACSL4) is directly correlated with aggressiveness in breast cancer and inversely correlated with estrogen receptor alpha (ERα) levels [2][3][4]. ACSL4 belongs to a five-member family of enzymes that esterifies mainly arachidonic acid (AA) into acyl-CoA [2][3][4][5]. Unlike the other ACSL isoforms, ACSL4 is encoded on the X chromosome and its expression is highest in adrenal cortex, ovary and testis [6][7][8][9][10], as well as in mouse and human cerebellum and hippocampus [11].…”

“…We have further demonstrated that ACSL4 can be silenced to reduce cell line aggressiveness. The role of ACSL4 in the development of growing tumors found further support when tumor growth was inhibited through the inhibition of ACSL4 expression [5]. However, even if the role of ACSL4 in mediating an aggressive phenotype in breast cancer is well accepted, its underlying mechanisms have been scarcely explored.…”