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.
Highlights
Breast cancer is a heterogeneous disease comprised of distinct molecular subtypes that can be generally characterized by the expression status of receptors for estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER2) and more recently, androgen (AR)
Tumors that are negative for expression of ER and PR and for amplification of HER2 expression are termed triple negative breast cancers (TNBC) and display a more aggressive phenotype that is not amenable to steroid hormone/HER2-based targeted therapies and has a worse prognosis than receptor positive cancer [1]
We have previously demonstrated that the fatty acid metabolic enzyme, long chain fatty acyl-CoA synthetase 4 (ACSL4) is differentially expressed in human breast cancer samples as a function of expression of ER and AR [7]
Summary
Breast cancer is a heterogeneous disease comprised of distinct molecular subtypes that can be generally characterized by the expression status of receptors for estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2(HER2) and more recently, androgen (AR). We have previously demonstrated that the fatty acid metabolic enzyme, long chain fatty acyl-CoA synthetase 4 (ACSL4) is differentially expressed in human breast cancer samples as a function of expression of ER and AR [7]. Previous studies have demonstrated that ACSL4 is overexpressed in both liver [10] and colon [11] cancer as well as in aggressive forms of breast cancer [7,12], and it has been suggested that metabolism of AA may play a role in mediating the effects of ACSL4 expression [12,13]. ACSL4 serves as one of many biomarkers of an aggressive breast cancer phenotype and/or resistance to hormonal interventions These data raise the question of the function of ACSL4 enzyme activity in mediating the aggressive phenotype associated with hormone independence. The investigation of the role of ACSL4 enzyme activity in mediating the aggressive phenotype associated with hormone independence may aid in the discovery of new therapeutic targets
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