title: Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells.
abstract: Statins, routinely used to treat hypercholesterolemia, selectively induce apoptosis in some tumor cells by inhibiting the mevalonate pathway. Recent clinical studies suggest that a subset of breast tumors is particularly susceptible to lipophilic statins, such as fluvastatin. To quickly advance statins as effective anticancer agents for breast cancer treatment, it is critical to identify the molecular features defining this sensitive subset. We have therefore characterized fluvastatin sensitivity by MTT assay in a panel of 19 breast cell lines that reflect the molecular diversity of breast cancer, and have evaluated the association of sensitivity with several clinicopathological and molecular features. A wide range of fluvastatin sensitivity was observed across breast tumor cell lines, with fluvastatin triggering cell death in a subset of sensitive cell lines. Fluvastatin sensitivity was associated with an estrogen receptor alpha (ERα)-negative, basal-like tumor subtype, features that can be scored with routine and/or strong preclinical diagnostics. To ascertain additional candidate sensitivity-associated molecular features, we mined publicly available gene expression datasets, identifying genes encoding regulators of mevalonate production, non-sterol lipid homeostasis, and global cellular metabolism, including the oncogene MYC. Further exploration of this data allowed us to generate a 10-gene mRNA abundance signature predictive of fluvastatin sensitivity, which showed preliminary validation in an independent set of breast tumor cell lines. Here, we have therefore identified several candidate predictors of sensitivity to fluvastatin treatment in breast cancer, which warrant further preclinical and clinical evaluation.
authors: Ontario Cancer Institute and Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors: Carolyn A
authors: CA
authors: Goard
authors: Michelle
authors: M
authors: Chan-Seng-Yue
authors: Peter J
authors: PJ
authors: Mullen
authors: Ariel D
authors: AD
authors: Quiroga
authors: Amanda R
authors: AR
authors: Wasylishen
authors: James W
authors: JW
authors: Clendening
authors: Dorota H S
authors: DH
authors: Sendorek
authors: Syed
authors: S
authors: Haider
authors: Richard
authors: R
authors: Lehner
authors: Paul C
authors: PC
authors: Boutros
authors: Linda Z
authors: LZ
authors: Penn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D008798:Mevalonic Acid / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D005229:Fatty Acids, Monounsaturated; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D007211:Indoles; D008798:Mevalonic Acid; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C506487:ESR1 protein, human; C489427:MYC protein, human