title: 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.
authors.affiliation: Department of Neuroscience & Physiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wu
authors.forename: Yirong
authors.initials: Y
authors.lastname: Li
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Wen
authors.forename: Max T
authors.initials: MT
authors.lastname: Marcus
authors.forename: Garrett
authors.initials: G
authors.lastname: Daniels
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Ling Hang
authors.initials: LH
authors.lastname: Wang
authors.forename: Xinxin
authors.initials: X
authors.lastname: Du
authors.forename: Sylvia
authors.initials: S
authors.lastname: Adams
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.forename: Marie E
authors.initials: ME
authors.lastname: Monaco
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003066:Coenzyme A Ligases; D047628:Estrogen Receptor alpha; D006728:Hormones; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; C506487:ESR1 protein, human; C508053:ERBB2 protein, human